Serotonin HTR1 Group and FOS Pathway (Homo sapiens)

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(Removed whitespace in PubMed identifiers.)
(fixed unconnected lines)
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   <Comment Source="WikiPathways-category">Cellular Process</Comment>
   <Comment Source="WikiPathways-category">Cellular Process</Comment>
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   <Graphics BoardWidth="938.0" BoardHeight="1602.0" />
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   <DataNode TextLabel="GNAI2" GraphId="b9df7" Type="Protein">
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   <DataNode TextLabel="RPS6K" GraphId="a6431" Type="GeneProduct">
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     <Comment>Functional Class RPS6K (ribosomal protein S6 kinase)</Comment>
-
    <Xref Database="Entrez Gene" ID="2771" />
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     <Graphics CenterX="816.9833333333333" CenterY="1312.9833333333333" Width="72.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="ff6600" />
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  </DataNode>
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-
  <DataNode TextLabel="Gb/g" GraphId="c67ec" Type="Complex">
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     <Comment></Comment>
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     <Xref Database="" ID="" />
     <Xref Database="" ID="" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="HTR1D" GraphId="bf366" Type="Protein">
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   <DataNode TextLabel="PKC" GraphId="ae0ca" Type="GeneProduct">
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     <Comment>protein kinase C</Comment>
-
    <Xref Database="Entrez Gene" ID="3352" />
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     <Attribute Key="org.pathvisio.model.BackpageHead" Value="PKC" />
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  </DataNode>
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  <DataNode TextLabel="GNAO1" GraphId="cedc2" Type="Protein">
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     <Xref Database="Entrez Gene" ID="50818" />
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-
    <Xref Database="Entrez Gene" ID="2775" />
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-
  </DataNode>
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-
  <DataNode TextLabel="HTR1E" GraphId="d7022" Type="Protein">
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    <Graphics CenterX="723.9833374023438" CenterY="202.98333740234375" Width="70.0333251953125" Height="37.0333251953125" ZOrder="32768" FontSize="10" Valign="Middle" Color="cc0000" />
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-
    <Xref Database="Entrez Gene" ID="3354" />
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-
  </DataNode>
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-
  <DataNode TextLabel="HTR1B" GraphId="c8d79" Type="Protein">
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-
    <Xref Database="Entrez Gene" ID="3351" />
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-
  </DataNode>
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-
  <DataNode TextLabel="Serotonin" GraphId="fb161" Type="Metabolite">
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-
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-
    <Xref Database="HMDB" ID="HMDB00259" />
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-
  </DataNode>
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-
  <DataNode TextLabel="HTR1A" GraphId="c3282" Type="Protein">
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-
     <Xref Database="Entrez Gene" ID="3350" />
+
   </DataNode>
   </DataNode>
   <DataNode TextLabel="GNAI1" GraphId="ae915" Type="Protein">
   <DataNode TextLabel="GNAI1" GraphId="ae915" Type="Protein">
Line 41: Line 19:
     <Xref Database="Entrez Gene" ID="2770" />
     <Xref Database="Entrez Gene" ID="2770" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="HTR1F" GraphId="de412" Type="Protein">
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   <DataNode TextLabel="ELK1" GraphId="b1b8a" Type="GeneProduct">
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+
    <Comment>ELK1, member of ETS oncogene family</Comment>
-
     <Xref Database="Entrez Gene" ID="3355" />
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     <Graphics CenterX="379.48333333333335" CenterY="1435.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
     <Xref Database="Entrez Gene" ID="2002" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="GNAI3" GraphId="d4c53" Type="Protein">
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   <DataNode TextLabel="RASGRF1" GraphId="b456e" Type="GeneProduct">
-
     <Graphics CenterX="669.4833333333333" CenterY="321.0" Width="69.03333333333333" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" />
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    <Comment>RAS protein-specific guanine nucleotide-releasing factor 1</Comment>
-
     <Xref Database="Entrez Gene" ID="2773" />
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     <Graphics CenterX="420.48333333333335" CenterY="760.9833333333333" Width="73.03333333333333" Height="46.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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     <Xref Database="Entrez Gene" ID="5923" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="PI3K" GraphId="d1342" Type="GeneProduct">
+
   <DataNode TextLabel="MAP2K6" GraphId="b8237" Type="GeneProduct">
-
     <Comment>phosphatidylinositol 3-kinase</Comment>
+
     <Comment>mitogen activated protein kinase kinase 6</Comment>
-
     <Graphics CenterX="855.4833333333333" CenterY="429.48333333333335" Width="69.03333333333333" Height="35.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="ff6600" />
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     <Xref Database="Entrez Gene" ID="5290" />
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     <Xref Database="Entrez Gene" ID="5608" />
-
  </DataNode>
+
-
  <DataNode TextLabel="PLC" GraphId="da47e" Type="GeneProduct">
+
-
    <Comment>phospholipase C</Comment>
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-
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-
    <Xref Database="" ID="" />
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-
  </DataNode>
+
-
  <DataNode TextLabel="PtdIns3P" GraphId="c56f6" Type="GeneProduct">
+
-
    <Comment>phosphatidylinositol 3,4,5-triphosphate</Comment>
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-
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-
    <Xref Database="" ID="" />
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   </DataNode>
   </DataNode>
   <DataNode TextLabel="1,2-Diacetin" GraphId="b91eb" Type="Metabolite">
   <DataNode TextLabel="1,2-Diacetin" GraphId="b91eb" Type="Metabolite">
Line 69: Line 39:
     <Xref Database="CAS" ID="102-62-5" />
     <Xref Database="CAS" ID="102-62-5" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="1,4,5-Insp3" GraphId="dbd89" Type="Metabolite">
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   <DataNode TextLabel="GNAI2" GraphId="b9df7" Type="Protein">
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     <Graphics CenterX="311.48333333333335" CenterY="565.9833333333333" Width="69.03333333333333" Height="40.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="009900" />
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     <Xref Database="CAS" ID="85166-31-0" />
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    <Xref Database="Entrez Gene" ID="2771" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAPK3" GraphId="bda33" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase 3</Comment>
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    <Xref Database="Entrez Gene" ID="5595" />
 +
  </DataNode>
 +
  <DataNode TextLabel="Ras" GraphId="beaf5" Type="GeneProduct">
 +
    <Comment>RAS oncogene homolog</Comment>
 +
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    <Xref Database="" ID="" />
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  </DataNode>
 +
  <DataNode TextLabel="HTR1D" GraphId="bf366" Type="Protein">
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    <Xref Database="Entrez Gene" ID="3352" />
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  </DataNode>
 +
  <DataNode TextLabel="HTR1A" GraphId="c3282" Type="Protein">
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 +
     <Xref Database="Entrez Gene" ID="3350" />
   </DataNode>
   </DataNode>
   <DataNode TextLabel="PDPK1" GraphId="c3d64" Type="GeneProduct">
   <DataNode TextLabel="PDPK1" GraphId="c3d64" Type="GeneProduct">
Line 78: Line 66:
     <Xref Database="Entrez Gene" ID="5170" />
     <Xref Database="Entrez Gene" ID="5170" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="ITPR1" GraphId="f7c77" Type="GeneProduct">
+
   <DataNode TextLabel="PtdIns3P" GraphId="c56f6" Type="GeneProduct">
-
     <Comment>inositol 1,4,5-triphosphate receptor 1</Comment>
+
     <Comment>phosphatidylinositol 3,4,5-triphosphate</Comment>
-
     <Graphics CenterX="313.98333333333335" CenterY="664.9833333333333" Width="70.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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-
    <Xref Database="Entrez Gene" ID="3708" />
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     <Xref Database="" ID="" />
-
  </DataNode>
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-
  <DataNode TextLabel="CALCIUM" GraphId="f039e" Type="Metabolite">
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-
     <Xref Database="CAS" ID="7440-70-2" />
+
-
  </DataNode>
+
-
  <DataNode TextLabel="PKC" GraphId="ae0ca" Type="GeneProduct">
+
-
    <Comment>protein kinase C</Comment>
+
-
    <Attribute Key="org.pathvisio.model.BackpageHead" Value="PKC" />
+
-
    <Graphics CenterX="848.4833333333333" CenterY="663.4833333333333" Width="73.03333333333333" Height="35.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="ff6600" />
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-
    <Xref Database="Entrez Gene" ID="50818" />
+
-
  </DataNode>
+
-
  <DataNode TextLabel="RASGRF1" GraphId="b456e" Type="GeneProduct">
+
-
    <Comment>RAS protein-specific guanine nucleotide-releasing factor 1</Comment>
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-
    <Graphics CenterX="420.48333333333335" CenterY="760.9833333333333" Width="73.03333333333333" Height="46.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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-
    <Xref Database="Entrez Gene" ID="5923" />
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   </DataNode>
   </DataNode>
   <DataNode TextLabel="RASGRP1" GraphId="c6568" Type="GeneProduct">
   <DataNode TextLabel="RASGRP1" GraphId="c6568" Type="GeneProduct">
Line 103: Line 76:
     <Xref Database="Entrez Gene" ID="10125" />
     <Xref Database="Entrez Gene" ID="10125" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="Ras" GraphId="beaf5" Type="GeneProduct">
+
   <DataNode TextLabel="Gb/g" GraphId="c67ec" Type="Complex">
-
     <Comment>RAS oncogene homolog</Comment>
+
     <Comment></Comment>
-
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     <Xref Database="" ID="" />
     <Xref Database="" ID="" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="RAP1A" GraphId="cc60d" Type="GeneProduct">
+
   <DataNode TextLabel="HTR1B" GraphId="c8d79" Type="Protein">
-
    <Comment>RAS-related protein-1a</Comment>
+
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     <Xref Database="Entrez Gene" ID="3351" />
-
     <Xref Database="Entrez Gene" ID="5906" />
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   </DataNode>
   </DataNode>
   <DataNode TextLabel="RHOA" GraphId="cbd30" Type="GeneProduct">
   <DataNode TextLabel="RHOA" GraphId="cbd30" Type="GeneProduct">
Line 118: Line 90:
     <Xref Database="Entrez Gene" ID="387" />
     <Xref Database="Entrez Gene" ID="387" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="MAP3K1" GraphId="f091e" Type="GeneProduct">
+
   <DataNode TextLabel="RAP1A" GraphId="cc60d" Type="GeneProduct">
-
     <Comment>mitogen activated protein kinase kinase kinase 1</Comment>
+
     <Comment>RAS-related protein-1a</Comment>
-
     <Graphics CenterX="433.98333333333335" CenterY="944.9833333333333" Width="70.03333333333333" Height="30.033333333333335" ZOrder="32768" FontSize="10" Valign="Middle" />
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     <Xref Database="Entrez Gene" ID="4214" />
+
     <Xref Database="Entrez Gene" ID="5906" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="BRAF" GraphId="e7898" Type="GeneProduct">
+
   <DataNode TextLabel="GNAO1" GraphId="cedc2" Type="Protein">
-
    <Comment>v-raf murine sarcoma viral oncogene homolog B1</Comment>
+
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     <Graphics CenterX="725.9833333333333" CenterY="944.4833333333333" Width="72.03333333333333" Height="37.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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     <Xref Database="Entrez Gene" ID="2775" />
-
     <Xref Database="Entrez Gene" ID="673" />
+
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="MAP2K3" GraphId="f88a3" Type="GeneProduct">
+
   <DataNode TextLabel="PI3K" GraphId="d1342" Type="GeneProduct">
-
     <Comment>mitogen activated protein kinase kinase 3</Comment>
+
     <Comment>phosphatidylinositol 3-kinase</Comment>
-
     <Graphics CenterX="300.48333333333335" CenterY="1078.9833333333333" Width="71.03333333333333" Height="38.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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-
     <Xref Database="Entrez Gene" ID="5606" />
+
     <Xref Database="Entrez Gene" ID="5290" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="MAP2K6" GraphId="b8237" Type="GeneProduct">
+
   <DataNode TextLabel="RPS6KA5" GraphId="d4bbc" Type="GeneProduct">
-
     <Comment>mitogen activated protein kinase kinase 6</Comment>
+
     <Comment>ribosomal protein S6 kinase, polypeptide 5</Comment>
-
     <Graphics CenterX="495.98333333333335" CenterY="1079.4833333333333" Width="72.03333333333333" Height="45.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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-
     <Xref Database="Entrez Gene" ID="5608" />
+
     <Xref Database="Entrez Gene" ID="9252" />
   </DataNode>
   </DataNode>
-
   <DataNode TextLabel="MAP2K2" GraphId="edc2e" Type="GeneProduct">
+
   <DataNode TextLabel="GNAI3" GraphId="d4c53" Type="Protein">
-
     <Comment>mitogen activated protein kinase kinase 2</Comment>
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     <Graphics CenterX="669.4833333333333" CenterY="321.0" Width="69.03333333333333" Height="38.0" ZOrder="32768" FontSize="10" Valign="Middle" />
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     <Graphics CenterX="671.4833333333333" CenterY="1080.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
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    <Xref Database="Entrez Gene" ID="2773" />
-
     <Xref Database="Entrez Gene" ID="5605" />
+
  </DataNode>
 +
  <DataNode TextLabel="HTR1E" GraphId="d7022" Type="Protein">
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 +
     <Xref Database="Entrez Gene" ID="3354" />
   </DataNode>
   </DataNode>
   <DataNode TextLabel="MAP2K1" GraphId="d7383" Type="GeneProduct">
   <DataNode TextLabel="MAP2K1" GraphId="d7383" Type="GeneProduct">
Line 147: Line 121:
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     <Xref Database="Entrez Gene" ID="5604" />
     <Xref Database="Entrez Gene" ID="5604" />
-
  </DataNode>
 
-
  <DataNode TextLabel="MAPK14" GraphId="eea31" Type="GeneProduct">
 
-
    <Comment>mitogen activated protein kinase 14</Comment>
 
-
    <Graphics CenterX="388.48333333333335" CenterY="1201.9833333333333" Width="71.03333333333333" Height="40.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="Entrez Gene" ID="1432" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="MAPK1" GraphId="fe3cb" Type="GeneProduct">
 
-
    <Comment>mitogen activated protein kinase 1</Comment>
 
-
    <Graphics CenterX="656.9833333333333" CenterY="1190.4833333333333" Width="74.03333333333333" Height="45.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="HGNC" ID="MAPK1" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="MAPK3" GraphId="bda33" Type="GeneProduct">
 
-
    <Comment>mitogen activated protein kinase 3</Comment>
 
-
    <Graphics CenterX="861.4833333333333" CenterY="1196.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="Entrez Gene" ID="5595" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="MAPKAPK2" GraphId="edbcf" Type="GeneProduct">
 
-
    <Comment>mitogen activated protein kinase 3</Comment>
 
-
    <Graphics CenterX="303.48333333333335" CenterY="1303.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="Entrez Gene" ID="9261" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="MAPKAPK3" GraphId="de99a" Type="GeneProduct">
 
-
    <Comment>mitogen-activated protein kinase-activated protein kinase 3</Comment>
 
-
    <Graphics CenterX="485.98333333333335" CenterY="1303.4833333333333" Width="74.03333333333333" Height="45.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="Entrez Gene" ID="7867" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="RPS6KA5" GraphId="d4bbc" Type="GeneProduct">
 
-
    <Comment>ribosomal protein S6 kinase, polypeptide 5</Comment>
 
-
    <Graphics CenterX="618.4833333333333" CenterY="1307.9833333333333" Width="73.03333333333333" Height="46.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="Entrez Gene" ID="9252" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="RPS6K" GraphId="a6431" Type="GeneProduct">
 
-
    <Comment>Functional Class RPS6K (ribosomal protein S6 kinase)</Comment>
 
-
    <Graphics CenterX="816.9833333333333" CenterY="1312.9833333333333" Width="72.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="ff6600" />
 
-
    <Xref Database="" ID="" />
 
-
  </DataNode>
 
-
  <DataNode TextLabel="ELK1" GraphId="b1b8a" Type="GeneProduct">
 
-
    <Comment>ELK1, member of ETS oncogene family</Comment>
 
-
    <Graphics CenterX="379.48333333333335" CenterY="1435.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 
-
    <Xref Database="Entrez Gene" ID="2002" />
 
   </DataNode>
   </DataNode>
   <DataNode TextLabel="SRF" GraphId="d8696" Type="GeneProduct">
   <DataNode TextLabel="SRF" GraphId="d8696" Type="GeneProduct">
Line 197: Line 131:
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     <Graphics CenterX="681.4833333333333" CenterY="1427.9833333333333" Width="71.03333333333333" Height="48.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
     <Xref Database="Entrez Gene" ID="2005" />
     <Xref Database="Entrez Gene" ID="2005" />
 +
  </DataNode>
 +
  <DataNode TextLabel="PLC" GraphId="da47e" Type="GeneProduct">
 +
    <Comment>phospholipase C</Comment>
 +
    <Graphics CenterX="311.98333333333335" CenterY="433.48333333333335" Width="68.03333333333333" Height="43.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="ff6600" />
 +
    <Xref Database="" ID="" />
 +
  </DataNode>
 +
  <DataNode TextLabel="1,4,5-Insp3" GraphId="dbd89" Type="Metabolite">
 +
    <Graphics CenterX="311.48333333333335" CenterY="565.9833333333333" Width="69.03333333333333" Height="40.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="009900" />
 +
    <Xref Database="CAS" ID="85166-31-0" />
 +
  </DataNode>
 +
  <DataNode TextLabel="HTR1F" GraphId="de412" Type="Protein">
 +
    <Graphics CenterX="853.9833374023438" CenterY="203.98333740234375" Width="70.0333251953125" Height="37.0333251953125" ZOrder="32768" FontSize="10" Valign="Middle" Color="cc0000" />
 +
    <Xref Database="Entrez Gene" ID="3355" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAPKAPK3" GraphId="de99a" Type="GeneProduct">
 +
    <Comment>mitogen-activated protein kinase-activated protein kinase 3</Comment>
 +
    <Graphics CenterX="485.98333333333335" CenterY="1303.4833333333333" Width="74.03333333333333" Height="45.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="7867" />
   </DataNode>
   </DataNode>
   <DataNode TextLabel="CREB1" GraphId="df2fc" Type="GeneProduct">
   <DataNode TextLabel="CREB1" GraphId="df2fc" Type="GeneProduct">
Line 202: Line 154:
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     <Graphics CenterX="811.9833333333333" CenterY="1421.4833333333333" Width="72.03333333333333" Height="49.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
     <Xref Database="Entrez Gene" ID="1385" />
     <Xref Database="Entrez Gene" ID="1385" />
 +
  </DataNode>
 +
  <DataNode TextLabel="BRAF" GraphId="e7898" Type="GeneProduct">
 +
    <Comment>v-raf murine sarcoma viral oncogene homolog B1</Comment>
 +
    <Graphics CenterX="725.9833333333333" CenterY="944.4833333333333" Width="72.03333333333333" Height="37.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="673" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAPKAPK2" GraphId="edbcf" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase 3</Comment>
 +
    <Graphics CenterX="303.48333333333335" CenterY="1303.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="9261" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAP2K2" GraphId="edc2e" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase kinase 2</Comment>
 +
    <Graphics CenterX="671.4833333333333" CenterY="1080.9833333333333" Width="71.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="5605" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAPK14" GraphId="eea31" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase 14</Comment>
 +
    <Graphics CenterX="388.48333333333335" CenterY="1201.9833333333333" Width="71.03333333333333" Height="40.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="1432" />
 +
  </DataNode>
 +
  <DataNode TextLabel="CALCIUM" GraphId="f039e" Type="Metabolite">
 +
    <Graphics CenterX="587.9833333333333" CenterY="658.4833333333333" Width="72.03333333333333" Height="37.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" Color="009900" />
 +
    <Xref Database="CAS" ID="7440-70-2" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAP3K1" GraphId="f091e" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase kinase kinase 1</Comment>
 +
    <Graphics CenterX="433.98333333333335" CenterY="944.9833333333333" Width="70.03333333333333" Height="30.033333333333335" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="4214" />
   </DataNode>
   </DataNode>
   <DataNode TextLabel="FOS" GraphId="f4dd2" Type="GeneProduct">
   <DataNode TextLabel="FOS" GraphId="f4dd2" Type="GeneProduct">
Line 207: Line 188:
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     <Graphics CenterX="598.9833333333333" CenterY="1550.4833333333333" Width="70.03333333333333" Height="43.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
     <Xref Database="Entrez Gene" ID="2353" />
     <Xref Database="Entrez Gene" ID="2353" />
 +
  </DataNode>
 +
  <DataNode TextLabel="ITPR1" GraphId="f7c77" Type="GeneProduct">
 +
    <Comment>inositol 1,4,5-triphosphate receptor 1</Comment>
 +
    <Graphics CenterX="313.98333333333335" CenterY="664.9833333333333" Width="70.03333333333333" Height="42.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="3708" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAP2K3" GraphId="f88a3" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase kinase 3</Comment>
 +
    <Graphics CenterX="300.48333333333335" CenterY="1078.9833333333333" Width="71.03333333333333" Height="38.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="Entrez Gene" ID="5606" />
 +
  </DataNode>
 +
  <DataNode TextLabel="Serotonin" GraphId="fb161" Type="Metabolite">
 +
    <Graphics CenterX="583.9833374023438" CenterY="90.98333740234375" Width="70.0333251953125" Height="37.0333251953125" ZOrder="32768" FontSize="10" Valign="Middle" Color="009900" />
 +
    <Xref Database="HMDB" ID="HMDB00259" />
 +
  </DataNode>
 +
  <DataNode TextLabel="MAPK1" GraphId="fe3cb" Type="GeneProduct">
 +
    <Comment>mitogen activated protein kinase 1</Comment>
 +
    <Graphics CenterX="656.9833333333333" CenterY="1190.4833333333333" Width="74.03333333333333" Height="45.03333333333333" ZOrder="32768" FontSize="10" Valign="Middle" />
 +
    <Xref Database="HGNC" ID="MAPK1" />
   </DataNode>
   </DataNode>
   <Interaction GraphId="a137a">
   <Interaction GraphId="a137a">
Line 215: Line 215:
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       <Point X="548.9666748046875" Y="100.24166870117188" GraphRef="fb161" RelX="-1.0" RelY="0.5" />
       <Point X="285.4666748046875" Y="190.22500610351562" GraphRef="c3282" RelX="-1.0" RelY="-0.5" />
       <Point X="285.4666748046875" Y="190.22500610351562" GraphRef="c3282" RelX="-1.0" RelY="-0.5" />
-
    </Graphics>
 
-
    <Xref Database="" ID="" />
 
-
  </Interaction>
 
-
  <Interaction GraphId="f67c5">
 
-
    <Comment>Binding HTR1B ---- serotonin</Comment>
 
-
    <Comment>Serotonin treatment of these cells has been reported to inhibit forskolin-stimulated cAMP accumulation in the 5-HT 1B -expressing cells, but not the parental HeLa cells (Hamblin et al., 1992 ). </Comment>
 
-
    <BiopaxRef>a8a</BiopaxRef>
 
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
 
-
      <Point X="566.4750061035156" Y="109.5" GraphRef="fb161" RelX="-0.5" RelY="1.0" />
 
-
      <Point X="480.5" Y="193.22500610351562" GraphRef="c8d79" RelX="1.0" RelY="-0.5" />
 
-
    </Graphics>
 
-
    <Xref Database="" ID="" />
 
-
  </Interaction>
 
-
  <Interaction GraphId="b835d">
 
-
    <Comment>Binding HTR1D ---- serotonin</Comment>
 
-
    <Comment>[3H]5-HT binding, in the presence of pindolol (to block 5-HT1A and 5-HT1B receptors) and mesulergine (to block 5-HT1C receptors), was specific, saturable, reversible, and of high affinity. </Comment>
 
-
    <BiopaxRef>bd4</BiopaxRef>
 
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
 
-
      <Point X="583.9833374023438" Y="109.5" GraphRef="fb161" RelX="0.0" RelY="1.0" />
 
-
      <Point X="584.4833374023438" Y="182.4666748046875" GraphRef="bf366" RelX="0.0" RelY="-1.0" />
 
-
    </Graphics>
 
-
    <Xref Database="" ID="" />
 
-
  </Interaction>
 
-
  <Interaction GraphId="b8c07">
 
-
    <Comment>Binding HTR1E ---- serotonin</Comment>
 
-
    <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. </Comment>
 
-
    <BiopaxRef>d9c</BiopaxRef>
 
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
 
-
      <Point X="601.4916687011719" Y="109.5" GraphRef="fb161" RelX="0.5" RelY="1.0" />
 
-
      <Point X="688.9666748046875" Y="193.72500610351562" GraphRef="d7022" RelX="-1.0" RelY="-0.5" />
 
-
    </Graphics>
 
-
    <Xref Database="" ID="" />
 
-
  </Interaction>
 
-
  <Interaction GraphId="b6462">
 
-
    <Comment>Binding HTR1F ---- serotonin,</Comment>
 
-
    <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. </Comment>
 
-
    <BiopaxRef>f3f</BiopaxRef>
 
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
 
-
      <Point X="619.0" Y="100.24166870117188" GraphRef="fb161" RelX="1.0" RelY="0.5" />
 
-
      <Point X="871.4916687011719" Y="185.4666748046875" GraphRef="de412" RelX="0.5" RelY="-1.0" />
 
-
    </Graphics>
 
-
    <Xref Database="" ID="" />
 
-
  </Interaction>
 
-
  <Interaction GraphId="b42e7">
 
-
    <Comment>Binding GNAI3 ---- HTR1A</Comment>
 
-
    <Comment>Taken together, these data show that low but not high concentrations of high-efficacy 5-HT(1A) agonists direct receptor signaling to Galpha(i3). In contrast, partial agonists favor h5-HT(1A) receptor signaling to Galpha(i3) over a wide concentration range, whereas inverse agonists inhibit constitutive Galpha(i3) activation.
 
-
</Comment>
 
-
    <BiopaxRef>b38</BiopaxRef>
 
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
 
-
      <Point X="337.9916687011719" Y="218.0" GraphRef="c3282" RelX="0.5" RelY="1.0" />
 
-
      <Point X="652.225" Y="302.0" GraphRef="d4c53" RelX="-0.5" RelY="-1.0" />
 
-
    </Graphics>
 
-
    <Xref Database="" ID="" />
 
-
  </Interaction>
 
-
  <Interaction GraphId="a698b">
 
-
    <Comment>Binding GNAI2 ---- HTR1D</Comment>
 
-
    <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
 
-
</Comment>
 
-
    <BiopaxRef>f8c</BiopaxRef>
 
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
 
-
      <Point X="480.5" Y="211.74166870117188" GraphRef="c8d79" RelX="1.0" RelY="0.5" />
 
-
      <Point X="669.4833333333333" Y="302.0" GraphRef="d4c53" RelX="0.0" RelY="-1.0" />
 
     </Graphics>
     </Graphics>
     <Xref Database="" ID="" />
     <Xref Database="" ID="" />
Line 291: Line 229:
     <Xref Database="" ID="" />
     <Xref Database="" ID="" />
   </Interaction>
   </Interaction>
-
   <Interaction GraphId="aaeb6">
+
   <Interaction GraphId="a2beb">
-
    <Comment>Binding GNAI2 ---- HTR1D</Comment>
+
     <Graphics ZOrder="12288" LineThickness="1.0" Color="999900">
-
    <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
+
       <Point X="675.4916666666667" Y="1213.0" GraphRef="fe3cb" RelX="0.5" RelY="1.0" />
-
</Comment>
+
       <Point X="798.975" Y="1291.9666666666667" GraphRef="a6431" RelX="-0.5" RelY="-1.0" ArrowHead="Arrow" />
-
    <BiopaxRef>f8c</BiopaxRef>
+
-
     <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
+
-
       <Point X="566.9750061035156" Y="219.5" GraphRef="bf366" RelX="-0.5" RelY="1.0" />
+
-
       <Point X="515.9833374023438" Y="317.9666748046875" GraphRef="b9df7" RelX="0.0" RelY="-1.0" />
+
     </Graphics>
     </Graphics>
     <Xref Database="" ID="" />
     <Xref Database="" ID="" />
   </Interaction>
   </Interaction>
-
   <Interaction GraphId="cadcd">
+
   <Interaction GraphId="a61f0">
-
     <Comment>Binding GNAI3 ---- HTR1D</Comment>
+
     <Comment>Binding GNAO1 ---- HTR1F</Comment>
-
     <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
+
     <Comment>11916537
 +
 
 +
Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.
 +
 
</Comment>
</Comment>
-
     <BiopaxRef>f8c</BiopaxRef>
+
     <Comment>14965240 Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.
-
    <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
+
-
      <Point X="601.9916687011719" Y="219.5" GraphRef="bf366" RelX="0.5" RelY="1.0" />
+
-
      <Point X="669.4833333333333" Y="302.0" GraphRef="d4c53" RelX="0.0" RelY="-1.0" />
+
-
    </Graphics>
+
-
    <Xref Database="" ID="" />
+
-
  </Interaction>
+
-
  <Interaction GraphId="ae40b">
+
-
    <Comment>Binding GNAO1 ---- HTR1D</Comment>
+
-
    <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
+
</Comment>
</Comment>
-
     <BiopaxRef>f8c</BiopaxRef>
+
     <BiopaxRef>f8d</BiopaxRef>
 +
    <BiopaxRef>f3f</BiopaxRef>
     <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
     <Graphics ZOrder="12288" LineThickness="1.0" Color="990099">
-
       <Point X="619.5" Y="200.98333740234375" GraphRef="bf366" RelX="1.0" RelY="0.0" />
+
       <Point X="871.4916687011719" Y="222.5" GraphRef="de412" RelX="0.5" RelY="1.0" />
-
       <Point X="769.4750061035156" Y="304.4666748046875" GraphRef="cedc2" RelX="-0.5" RelY="-1.0" />
+
       <Point X="804.4916687011719" Y="304.4666748046875" GraphRef="cedc2" RelX="0.5" RelY="-1.0" />
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     </Graphics>
     <Xref Database="" ID="" />
     <Xref Database="" ID="" />
   </Interaction>
   </Interaction>
-
   <Interaction GraphId="bcb29">
+
   <Interaction GraphId="a693b">
-
     <Comment>G protein beta/gamma</Comment>
+
     <Comment>DirectRegulation Ras --+&gt; BRAF</Comment>
-
     <Comment>Binding Gb/g ---- GNAO1</Comment>
+
     <Comment>14984580 BRAF, a serine/threonine kinase, is a component of the retrovirus-associated sequence (RAS)-RAF-extracellular-regulated protein kinase (ERK)-MAP kinase signal transduction pathway mediating signals from RAS to ERK.  
-
    <Comment>11124982 If the Getagamma subunits served as linkers, dialyzing Galpha o should have bound the Getagamma subunits, prevented their activation, and thus depolarized the cell.  
+
-
(Tissue: plasma) Of interest, when mutations that disrupt interactions of Ga o with G��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩ? are combined with a G2A mutation to inhibit N -myristoylation, palmitoylation is no longer evident - even when plasma membrane targeting is apparently maintained ( Wang et al. , 1999b ).  
+
8887643 Unexpectedly, yeast two-hybrid binding analyses showed that although both Ras and TC21 could interact with the isolated Ras-binding domain of Raf-1, only Ras interacted with full-length Raf-1, A-Raf, or B-Raf.  
 +
11032810 In this report, we examined the potential phosphorylation sites in B-Raf responsible for Ras-induced activation.
-
9065414 To analyze the interaction of Getagamma complex with Galpha o , 10 ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩg of Geta, 10 ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩg of Ggamma, and 10 ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩg of Galpha o DNAs were transfected.  
+
11856330 However, clear inhibition of the interaction between Ras and B-Raf was not observed (Fig. 3C ).  
-
9346921 It has been shown that Galpha o forms a complex with Getagamma in HEK 293 cells ( 44 ).  
+
11283246 In UT7-Mpl cells, Raf-1 but not B-Raf mediates the Ras-induced activation of Elk1.  
-
+
-
7761832 A peptide encoding residues 956 to 982 of adenylyl cyclase 2 specifically blocked G beta gamma stimulation of adenylyl cyclase 2, phospholipase C-beta 3, potassium channels, and beta-adrenergic receptor kinase as well as inhibition of calmodulin-stimulated adenylyl cyclases, but had no effect on interactions between G beta gamma and G alpha o.
+
8687465 (Organ: brain) These results suggest that there is a subtle structural difference in requirements for the interaction of Ras with Raf-1 and B-Raf.  
-
</Comment>
+
-
    <BiopaxRef>ed0</BiopaxRef>
+
-
    <BiopaxRef>bae</BiopaxRef>
+
-
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    <Comment>G protein beta/gamma</Comment>
+
-
    <Comment>Binding Gb/g ---- GNAI1</Comment>
+
-
    <Comment>12488455 However, the extent of Getagamma binding to GST-Galphai 3-GDP was always greater than to GST (Fig. 3 , A and B ).  
+
-
(Tissue: neuroendocrine, CellLineName: AtT20)  
+
8617731 (Organ: brain) In rat brain the association of MEK1 with Ras is dependent on B-Raf, not on Raf-1( 14 ) .
 +
 
 +
7744815 (Organ: brain) GTP-Ras directly interacts with B-Raf (13, 14) and c-Raf-1 ( 19 , 20 , 21 , 22 , 23 , 24 ) .
 +
 
 +
11696358 (Organ: kidney, CellLineName: 293) On the other hand, Ras-dependent extracellular signal-regulated kinase/mitogen-activated protein kinase kinase stimulator (a complex of B-Raf and 14-3-3) failed to activate Raf-1 in our cell-free system.
 +
 
 +
8622647 (CellLineName: NIH 3T3) B-Raf was not detectably tyrosine phosphorylated, membrane localized, or further activated upon Ras transformation, even though B-Raf has been shown to bind to Ras in vitro.
</Comment>
</Comment>
-
     <Comment>15488193 (Tissue: neuroendocrine, CellLineName: AtT20) The particular sequences chosen have been demonstrated to bind selectively to the GDP-bound form of Galphai, but not Galphao, and preclude association of Gbetagamma and Galphai subunits.
+
     <BiopaxRef>e36</BiopaxRef>
-
</Comment>
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    <BiopaxRef>a26</BiopaxRef>
-
     <BiopaxRef>ec8</BiopaxRef>
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     <BiopaxRef>ba7</BiopaxRef>
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-
     <Comment>Binding GNAI1 ---- HTR1E</Comment>
+
     <Comment>Binding GNAI2 ---- HTR1D</Comment>
-
     <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.
+
     <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
</Comment>
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     <Comment>Binding GNAI2 ---- HTR1E</Comment>
+
     <Comment>Regulation PKC --+&gt; RAP1A</Comment>
-
     <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.  
+
     <Comment>10629034 (CellType: platelet) Here we show that thrombin induces a second phase of Rap1 activation, which is mediated by protein kinase C (PKC).  
 +
 
 +
15078882 (CellType: platelet) Intracellular Ca2+ and protein kinase C have been proposed to mediate agonist-induced Rap1B activation in platelets ( 10 , 11 ).  
</Comment>
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     <Comment>Binding GNAI3 ---- HTR1E</Comment>
+
     <Comment>ChemicalReaction 1,2-Diacetin; PLC; 1,4,5-Insp3</Comment>
-
     <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.  
+
     <Comment>The PLC that hydrolyzes PC-PLC generates the products phosphocholine and DAG.  
</Comment>
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-
     <Comment>Binding GNAO1 ---- HTR1E</Comment>
+
     <Comment>ProtModification MAPK3 --+&gt; ELK4</Comment>
-
     <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.  
+
     <Comment>MedLine Reference  9130707 
 +
Sentence  Sap-1a is phosphorylated by ERK-1.
 +
Source  Ariadne Pathways 
</Comment>
</Comment>
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-
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   <Interaction GraphId="a962a">
-
     <Comment>Binding GNAI1 ---- HTR1F</Comment>
+
     <Comment>ProtModification BRAF --+&gt; MAP2K2,</Comment>
-
     <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.  
+
     <Comment>12801936 (Organ: pituitar, Tissue: epithelia) ERKs are activated by the mitogen-activated protein kinase kinases, MEK1 and MEK2, which are activated by the MEK kinases, Raf-1, A-Raf, and B-Raf.
 +
 
 +
10783132 (Organ: lung, Tissue: epithelia) Raf-1 and B-Raf are serine/threonine-protein kinases that selectively phosphorylate and activate MEK1 and MEK2 ( 22 ).
 +
 
 +
8621389 Raf-1 and B-Raf are serine/threonine-protein kinases that selectively phosphorylate and activate MEK 1 and MEK 2( 14 , 15 , 16 , 17 ) .
 +
 
 +
12351703 Next, actions of the D2 receptor on c-Raf and B-Raf, which phosphorylate MEK1/2, were examined (Fig. 10 ).
 +
 
 +
8668348 We show that, consequently, B-Raf interacts with MEK-1 and MEK-2 with a better affinity than does c-Raf-1, thus strengthening the notion that B-Raf is a stronger MEK activator than c-Raf-l.
 +
 
 +
15153095 (CellType: neural) In addition, MEK1/2 can be activated by B-Raf, a neuron-enriched isoform of Raf, which is in turn activated by a cAMP-responsive Ras homologue called Rap-1 [ 41 ].
 +
 
 +
9733801 (CellLineName: COS I) A , quantitative analysis of the interaction of Raf-1 and B-Raf with MEK-1 and MEK-2 in the yeast two-hybrid system.
 +
 
 +
12738761 Next, actions of the D2 receptor on c-Raf and B-Raf, which phosphorylate MEK1/2, were examined (Fig. 10 ).  
</Comment>
</Comment>
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-
     <Comment>Binding GNAI3 ---- HTR1F</Comment>
+
     <Comment>Binding GNAI2 ---- HTR1D</Comment>
-
     <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.
+
     <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
</Comment>
</Comment>
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     <Comment>Binding GNAO1 ---- HTR1F</Comment>
+
     <Comment>Binding GNAI1 ---- HTR1F</Comment>
-
     <Comment>11916537
+
     <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.  
-
 
+
-
Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.  
+
-
 
+
</Comment>
</Comment>
-
    <Comment>14965240 Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.
 
-
</Comment>
 
-
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-
    <Comment>MolTransport GNAI2 --+&gt; Gb/g,</Comment>
+
-
    <Comment>Alpha-thrombin-mediated phosphatidylinositol 3-kinase activation through release of Gbetagamma dimers from Galphaq and Galphai2.
+
-
</Comment>
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-
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    <Comment>MolTransport GNAI3 --+&gt; Gb/g</Comment>
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-
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-
    <Comment>DirectRegulation Gb/g --+&gt; PI3K</Comment>
+
-
    <Comment>11879201 Type IB phosphoinositide 3OH-kinase (PI3K) is activated by G-protein betagamma subunits (Gbetagammas).
+
-
 
+
-
10642513 A novel p110gamma PI-3K was reported to be activated by G(i)-coupled receptors via Gbetagamma subunits.
+
-
 
+
-
11400324 Recent studies have demonstrated that PI3-Kinase can be activated by G beta gamma, but not by G alpha subunit.
+
-
 
+
-
11673483 Gbetagamma coimmunoprecipitated with PLCbeta and phosphatidylinositol 3-kinase.
+
-
 
+
-
14575867 (CellType: melanophore) In Xenopus aggregation, we suggest that melatonin stimulation of the Mel1c receptor via G(beta gamma) activates PI3-K that, directly or indirectly via MAPK, activates PDE.
+
-
 
+
-
7896797 (CellType: platelet) Recent reports indicate that cytosolic PI 3-Ks can also be activated by the beta gamma subunits of heterotrimeric G-proteins (G beta gamma).
+
-
 
+
-
12181454 Moreover, it is generally accepted that Getagamma is involved in PI3K activation (Clapham and Neer, 1997 ; Vanhaesebroeck et al., 1997 ).
+
-
 
+
-
12796499 It should be noted that it has been well established that PI3K can be activated by the Getagamma-coupled signaling pathway ( 23 – 25 ).
+
-
 
+
-
12529253 (Tissue: egg) Moreover, it is generally accepted that Getagamma is involved in PI3K activation ( 1 , 15 ).
+
-
 
+
-
10788495 Identity and purity of recombinant PI3Ks, PLC isozymes, and Getagamma dimers.
+
-
 
+
-
</Comment>
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-
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-
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-
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-
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-
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-
    <Comment>Regulation PtdIns3P --+&gt; PDPK1</Comment>
+
-
    <Comment>Phosphorylation of Akt at threonine 308 is catalyzed by the ubiquitously expressed and constitutively activated phosphatidylinositol 3,4,5-triphosphate-dependent protein kinase-1 (PDK-1) ( 34 , 35 ).
+
-
</Comment>
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-
    <Xref Database="" ID="" />
+
-
  </Interaction>
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-
  <Interaction GraphId="eb846">
+
-
    <Comment>ProtModification PDPK1 --+&gt; PKC</Comment>
+
-
    <Comment>11035106 (Tissue: alveola, CellType: macrophage) We then evaluated whether or not PDK-1 might be involved in PKC activation by examining complex formation.
+
-
 
+
-
12169624 Interestingly, however, PDK1 can only interact with full-length PKC when it is not phosphorylated at its hydrophobic motif and phosphorylation of this motif was shown to somehow mask this region, preventing it from interacting with PDK1 ( Gao et al ., 2001 ).
+
-
 
+
-
11500364 Furthermore, the data appear to exclude a role for members of the PKC family that are also regulated by PDK1 in the regulation of 4E-BP1 phosphorylation: an earlier report indicated a role in this for PKCdelta ( Kumar et al ., 2000 ).
+
-
 
+
-
10330161 (CellLineName: PC 12) Very recently, PKCdelta ( 27 ) and PKCeta ( 5 , 27 ) have been shown to be activated by a wortmannin-sensitive, PI-3-kinase-dependent pathway via phosphorylation of PKC by PDK1.
+
-
 
+
-
11376011 To probe whether the interaction of protein kinase C with PDK-1 was direct or mediated by a scaffold protein, we examined the interaction of pure PDK-1 with pure protein kinase C.
+
-
 
+
-
11971024 Complicating the picture, the PIP 3 -dependent PDK1, besides playing a critical role in activating PKB, has also been shown to phosphorylate/activate various PKC isoforms ( 27 , 28 , 29 ).
+
-
 
+
-
10438924 Recent work has shown that PDK1 phosphorylates and activates the p70 S6K kinase ( 86 ), the Sgk protein kinase ( 87 ), and the isoform of protein kinase C (PKC) ( 88 ).
+
-
 
+
-
10744767 In this communication, we addressed whether the phosphorylation of protein kinase C by PDK-1 is conformationally regulated.
+
-
 
+
-
10861044 PDK-1 has been shown to phosphorylate/activate various PKC isoforms ( 24 , 25 , 26 , 27 , 28 ).
+
-
 
+
-
</Comment>
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-
    <BiopaxRef>f98</BiopaxRef>
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    <BiopaxRef>a47</BiopaxRef>
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-
    <BiopaxRef>cb6</BiopaxRef>
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-
     <Comment>Regulation PKC --+&gt; RAP1A</Comment>
+
     <Comment>Binding GNAO1 ---- HTR1E</Comment>
-
     <Comment>10629034 (CellType: platelet) Here we show that thrombin induces a second phase of Rap1 activation, which is mediated by protein kinase C (PKC).  
+
     <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.  
-
 
+
-
15078882 (CellType: platelet) Intracellular Ca2+ and protein kinase C have been proposed to mediate agonist-induced Rap1B activation in platelets ( 10 , 11 ).  
+
</Comment>
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-
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    <Comment>DirectRegulation RASGRP1 --+&gt; RAP1A</Comment>
+
-
    <Comment>11292831 (Organ: brain, CellLineName: PC12D) We next showed in coimmunoprecipitation experiments that CalDAG-GEFI forms a complex with Rap1 and B-Raf following exposure to carbachol or calcium ionophore and the DAG analogue OAG (Fig. 8 ).
+
-
 
+
-
9789079 (CellLineName: 293T) Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells.
+
-
 
+
-
14702343 (CellLineName: JURKAT) Our results have demonstrated that forced expression of CalDAG-GEFI activated endogenous Rap1 and augmented adhesion to ICAM-1 in response to TCR stimulation.
+
-
 
+
-
10835426 (CellLineName: 293T) As reported previously ( 15 , 16 ), CalDAG-GEFI activated Rap1 and, to a lesser extent, R-Ras, and CalDAG-GEFII activated both Ha-Ras and R-Ras
+
-
</Comment>
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-
    <Comment>DirectRegulation RASGRF1 --+&gt; RAP1A</Comment>
+
-
    <Comment>10196191 In contrast, mutation of residue 70 does not affect the interaction of Cdc25 Mm with Rap1A and even increases the activity toward Ras(Q70L) almost 2-fold, indicating that residue 70 has an important role in the interaction with C3G but not as much with Cdc25 Mm .
+
-
 
+
-
15572660 (Tissue: endothelial) However, RasGRP2 is a Rap1 activator and not a Ras activator, whereas RasGRP3 is an activator of Ras and Rap1.
+
-
 
+
-
15213298 RasGRP3 activates both Ras and Rap1 (Yamashita et al., 2000 ), and RasGRP4 activates Ras (Reuther et al., 2002 ; Yang et al., 2002 ).
+
-
</Comment>
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-
    <BiopaxRef>deb</BiopaxRef>
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   <Interaction GraphId="ad624">
-
     <Comment>DirectRegulation CALCIUM --+&gt; RASGRP1,</Comment>
+
     <Comment>MolTransport GNAI3 --+&gt; Gb/g</Comment>
-
    <Comment>CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide exchange factors (GEFs) that can be stimulated by calcium and diacylglycerol and that can activate small GTPases, including Ras and Rap1, molecules increasingly recognized as having signaling functions in neurons.
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-
     <Comment>DirectRegulation CALCIUM --+&gt; PKC,</Comment>
+
     <Comment>Binding GNAO1 ---- HTR1D</Comment>
-
     <Comment>10713965 PDBu-induced activation of PKC promotes the priming of secretory granules, thereby enhancing the efficacy for Ca2+ to trigger fusion/exocytosis.
+
     <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
-
 
+
-
8429046 It appears, therefore, that the binding of Ca2+ to PKC requires a complex tertiary structure in the regulatory domain.
+
-
 
+
-
1313322 (Tissue: articular cartilage, CellType: chondrocyte) The activity of various subspecies of protein kinase C (PKC) in chondrocytes derived from rodent costal cartilage and bovine articular cartilage has been determined and the role of PKC in GAG synthesis as well as the possible interactions of PKC with calcium- or cyclic AMP (cAMP)-dependent systems in the synthesis of GAG.
+
-
 
+
-
10325235 (CellType: cardiomyocyte) Phorbol ester-sensitive PKC isoforms were detected at very low levels in caveolae fractions prepared from unstimulated cardiomyocytes; phorbol 12-myristate 13-acetate (PMA) (but not 4alpha-PMA, which does not activate PKC) recruited calcium-sensitive PKCalpha and novel PKCdelta and PKCepsilon to this compartment.
+
-
 
+
-
9725212 (CellType: t cell) Since cyclosporin does not have any effect on cytosolic Ca 2+ levels and thus does not interfere with the interaction between PKC and Ca 2+ , we tested the effect of an inhibitor of intracellular Ca 2+ redistribution, TMB-8 ( 36 ), on TCR cross-linking-induced AICD.
+
-
 
+
-
10751227 (Tissue: mesangia) DAG can directly activate classical types of PKC by interacting with its lipid-binding domain, and IP3 can indirectly activate PKC by increasing intracellular Ca2+, which interacts with the PKC Ca2+-binding domain.
+
-
 
+
-
11342594 Synaptotagmins are transmembrane proteins with a short NH2-terminal ectodomain, a single transmembrane region, and two highly conserved, independently folding Ca2+-binding C2 domains (C2A and C2B) homologous to the C2 regulatory region of protein kinase C.
+
-
 
+
-
7836388 At odds with the concept of calcium modulation of lipid binding, these authors considered phospholipids as modulators for the binding of calcium to PKC( 31 , 34 ) .
+
-
 
+
-
9852158 The four inhibitors of PKC all accelerated the breakdown of the F-actin network observed after 5 min (Fig. 6 D ) and 30 min (Fig. 6 E ) in 0 Ca 2+ .
+
-
 
+
-
9218480 These data reveal that the negative charge on the carboxyl terminus of protein kinase C contributes to the interaction of protein kinase C with Ca 2+ .
+
-
 
+
</Comment>
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-
     <Comment>DirectRegulation 1,2-Diacetin --+&gt; PKC</Comment>
+
     <Comment>ProtModification MAP3K1 --+&gt; MAP2K3</Comment>
-
     <Comment>The "conventional" PKC isoforms ( , ?1, ?II, and ) are regulated by DAG, which binds the C1 domain, and by Ca2+, which binds the C2 domain.
+
     <Comment>9006914 Activation of the JNK/p38 protein kinases involves a kinase cascade in which the upstream activator MAP kinase kinase kinase (MEKK) phosphorylates and activates MAP kinase kinase 3, 4, and 6 (MKK 3, 4 and 6), which in turn phosphorylate and activate JNK and p38 MAP kinases ( 34-37 ).  
-
</Comment>
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-
    <Comment>Regulation 1,2-Diacetin --+&gt; RASGRP1,</Comment>
+
-
    <Comment>11880369 Diacylglycerol has been shown to regulate RasGRP subcellular location and catalytic activity ( 8 , 15-17 ).  
+
-
15879121 Y775 and Y783 are therefore identified as the primary regulatory tyrosines for both the IP 3 -mediated Ca 2+ flux and the DAG-mediated activation of the PKC/RasGRP pathway.  
+
9065412 Although Mekk1 could phosphorylate Mek1, Mek2, Sek1, and MKK3, when it was expressed at physiological levels, only SAP kinase was markedly activated without Hog ( 13 ) or Erk ( 34 ) stimulation.  
-
17492052 (CellType: platelet) We have recently identified Ca 2+ and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI; also referred to as RasGRP2) as crucial for ��Ω��ΩΩ��Ω��ΩΩΩ 3 integrin activation in platelets ( 15 ).  
+
10358048 Each cascade consists of a three kinase module: a MAP kinase, a MAP kinase/ERK kinase (MEK ) that activates the MAP kinase, and a MEK kinase (MEKK ) that activates the MEK ( 3 ).  
-
11395491 (CellType: t cell) IP 3 binds receptors that regulate the release of stored Ca 2+ , whereas DAG is required to activate proteins such as protein kinase C and Ras guanyl nucleotide releasing protein (RasGRP) ( 17-19 ).  
+
10644746 (CellLineName: 293T) Cotransfection of the cells with ASK-1 , a MEK kinase known to activate MEK3, resulted in increases in luciferase activity of up to 10-fold (data not shown).  
-
15795236 (CellType: t cell) An increase in inositol ( 1 , 4 , 5 ) tris phosphate levels results in release of calcium from intracellular stores, whereas increased diacylglycerol results in stimulation of PKC and RasGRP (for review see reference 30 ).  
+
11304531 (CellLineName: HEK 293) For example, MEKK1 preferentially activates MKK3, MKK4, and MKK6 rather than MKK7 ( 39 ), whereas MEKK4 activates MKK3 and MKK6 rather than MKK4 ( 40 ).  
-
11292831 (CellLineName: PC12D) Together, these data define a novel signaling pathway for M 1 mAChR , where increases in Ca 2+ and diacylglycerol stimulate the sequential activation of CalDAG-GEFI , Rap1, and B-Raf, resulting in the activation of MEK and ERK1/2.  
+
11306453 In response to extracellular stimuli, MEKK1 is a strong activator of MKK4 and MKK7, and a weaker activator of MKK3 and MKK6 (Fig. 1 A ; Ref. 19 ).  
-
14532295 (CellType: b cell, CellLineName: ramos) Conversely, diacylglycerol both activates RasGRP1 and causes the activation and translocation of diacylglycerol kinase, which abrogates the activation of the GRP protein ( 43 , 44 ).  
+
7797459 MEKK1 can activate MKK4, MKK3, MEK1, and MEK2( 27 , 46 , 47 ) , suggesting that MEKKs have a broader substrate specificity than MEKs.  
-
14557275 (CellLineName: MOCK) In this regard, it has been reported that DAG kinase zeta phosphorylates specifically localized DAG molecules, thereby controlling the activation of the DAG-activated signaling protein RasGRP and H-Ras ( 20 ).  
+
11956220 MEKK1 can also activate MEK3, which subsequently activates p38 MAPKs ( 30 , 31 ).  
-
11257115 (CellLineName: Rat2) It is important then that cells regulate the DAG that activates RasGRP.  
+
11698415 (CellType: keratinocyte) MEKK1, in turn, activates MEK1, MEK3, and MEK7 ( 17 , 34 ).  
-
11352924 (Organ: brain) DAG produced in response to these external stimuli activates PKC and the guanine nucleotide exchange factors vav and RasGRP ( 39 , 40 ).  
+
9639556 (CellType: keratinocyte) MEKK1, however, was found to activate additional MAPKKs, including Jun amino (N)-terminal kinase kinase 1(MKK4) [JNKK1(MKK4)] (DA?A�rijard et al. 1995 ; Lin et al. 1995 ), JNKK2(MKK7) (Wu et al. 1997 ), MKK3, and MKK6 (Stein et al. 1996 ).  
</Comment>
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-
     <Comment>DirectRegulation Gb/g --+&gt; PLC</Comment>
+
     <Comment>Binding GNAI3 ---- HTR1A</Comment>
-
     <Comment>Activation of Gi/o-coupled receptors induces dissociation of Galpha from Getagamma, which activates phospholipase C and a resultant generation of the second messengers D - myo -inositol 1,4,5-trisphosphate and diacylglycerol, leading to activation of protein kinase C (PKC).  
+
     <Comment>Taken together, these data show that low but not high concentrations of high-efficacy 5-HT(1A) agonists direct receptor signaling to Galpha(i3). In contrast, partial agonists favor h5-HT(1A) receptor signaling to Galpha(i3) over a wide concentration range, whereas inverse agonists inhibit constitutive Galpha(i3) activation.  
</Comment>
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     <Comment>ChemicalReaction 1,2-Diacetin; PLC; 1,4,5-Insp3</Comment>
+
     <Comment>ProtModification BRAF --+&gt; MAP2K1,</Comment>
-
     <Comment>The PLC that hydrolyzes PC-PLC generates the products phosphocholine and DAG.
+
     <Comment>12167697 Reactions were immunoblotted as indicated. (B) The reactions were identical to those for panel A, except that recombinant WT-MEK1 activated by recombinant B-Raf in vitro was used to phosphorylate the immunoprecipitated ERKs.  
-
</Comment>
+
-
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-
    <Comment>ChemicalReaction 1,2-Diacetin; PLC; 1,4,5-Insp3,</Comment>
+
-
    <Comment>The PLC that hydrolyzes PC-PLC generates the products phosphocholine and DAG.
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-
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    <Comment>DirectRegulation 1,4,5-Insp3 --+&gt; ITPR1</Comment>
+
-
    <Comment>11274965 We compared the effects of oxidizing reagents, in particular thimerosal, and of cyclic ADP-ribose (cADPR) on IP3 binding to the various IP3R isoforms.  
+
-
8633244 IP3 activates the IP3 receptor (IP3R), an intracellular calcium release channel on the endoplasmic reticulum.  
+
12351703 V., Calleja V., Scimeca J.-C., Filloux C., Calothy G. and Van Obberghen E. (1995) Regulation of the MAP kinases cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP.  
-
9688849 Thus, besides affecting the binding of IP3 to IP3R ( 49 , 50 ), the effects of Mg2+ on the single-channel properties of the IP3R may therefore contribute to the control of temporal and spatial patterns of Ca2+ release from intracellular stores.  
+
15153095 In addition, MEK1/2 can be activated by B-Raf, a neuron-enriched isoform of Raf, which is in turn activated by a cAMP-responsive Ras homologue called Rap-1 [ 41 ].  
-
11017917 (CellType: myocyte) IP3 releases Ca2+ from intracellular stores by opening specific Ca2+ channels (IP3R).  
+
14570902 The activated Ras and Rap1 stimulate sequential activation of Raf serine/threonine kinases C-Raf and B-Raf, respectively, which in turn activate MEK1/ERKs.  
-
12621039 (Organ: cerebellar, CellType: Brain Stem, CellLineName: ng108-15) It has been reported that IP3 binding to the IP3R is not cooperative ( 31 , 33 ), and the same property holds true for the wild-type receptor and all of the mutant receptors except D1-223 expressed in R23-11 cells (Table I ).
+
7559496 We also showed that B-Raf interacts in vivo with Mek-1 and phosphorylates this protein on both serine 218 and 222( 25 ) .  
-
</Comment>
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    <Comment>MolTransport ITPR1 --+&gt; CALCIUM,</Comment>
+
-
    <Comment>8571671 The molecular basis of the complex Ca2+ signals is the regenerative character of the inositol trisphosphate receptor (InsP3R) responsible for the release of Ca2+ from intracellular stores.  
+
-
8765993 A Ca2+-mediated conformational change of the InsP3R is most likely the key feature of the mechanism for quantal Ca2+ release, but the exact mode of operation remains unclear.  
+
15572664 Activated B-Raf activates MEK1, which in turn phosphorylates and activates ERK1/2 for a sustained period.  
-
9675184 The InsP3R channels release Ca2+ from intracellular compartments to generate localized Ca2+ transients that govern a myriad of cellular signaling phenomena (Berridge, 1993. Nature. 361:315-325; Joseph, 1996. Cell Signal. 8:1-7; Kume et al., 1997. Science. 278:1940-1943; Berridge, 1997. Nature. 368:759-760). express multiple InsP3R isoforms, but only the function of the single type 1 InsP3R channel is known.  
+
8668348 We show that, consequently, B-Raf interacts with MEK-1 and MEK-2 with a better affinity than does c-Raf-1, thus strengthening the notion that B-Raf is a stronger MEK activator than c-Raf-l.  
-
15201137 (Tissue: skeletal) Agonist-induced increase in gene expression and calcium release were blocked by the InsP(3)R inhibitors 2-aminoethoxydiphenyl borate and xestospongin C.  
+
7731720 However, there has been no evidence for a direct interaction between B-Raf and Mek-1.  
-
15677321 Addition of native GAPDH and NAD(+) to WT IP(3)R stimulates calcium release, whereas no stimulation occurs with C992S/995S IP(3)R that cannot bind GAPDH.
+
12218141 (CellType: neutrophil) This is consistent with other findings that C5a causes the activation of Raf-1 and B-Raf, which are upstream stimulators of MEK-1 in human neutrophils, with a peak of activation at 5 min, followed by suppressed activation thereafter ( 38 ).  
-
 
+
-
9607940 The inositol (1,4,5)-trisphosphate receptor (InsP3R) mediates Ca2+ release from intracellular stores in response to generation of second messenger InsP3.
+
-
 
+
-
7533300 (Tissue: skeletal muscle) Disrupting the IP3R-FKBP12 interaction increases Ca2+ flux through IP3R, an effect that is reversed by added FKBP12.
+
-
 
+
-
9831561 The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) acts as a Ca2+ release channel on internal Ca2+ stores.
+
-
 
+
-
10096607 Inositol 1,4,5-trisphosphate receptors (IP3R) are mediators of second messenger-induced intracellular calcium release.
+
-
 
+
-
12491767 IP3receptor (IP3R) works as an IP3 induced Ca2+ release channel and requires IP3 and Ca2+ as coagoinist.  
+
</Comment>
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     <Comment>DirectRegulation 1,2-Diacetin --+&gt; RASGRF1</Comment>
+
     <Comment>Binding HTR1F ---- serotonin,</Comment>
-
     <Comment>RasGRP3 localization and activity is regulated by DAG, and this interaction is mimicked by the phorbol ester PMA.  
+
     <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. </Comment>
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-
     <Comment>DirectRegulation CALCIUM --+&gt; RASGRF1</Comment>
+
     <Comment>PromoterBinding CREB1 --+&gt; FOS</Comment>
-
     <Comment>We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo in response to elevated calcium levels.
+
     <Comment>Source  Ariadne Pathways 
-
</Comment>
+
MedLine Reference  9528766:10034 
-
    <BiopaxRef>a17</BiopaxRef>
+
Sentence  In addition to the TCF-SRF complex, the cyclic AMP response element binding protein (CREB), which binds to three separate sequences within the c- fos promoter distinct from the SRE, appears to be required for NGF induction of c- fos transcription ( 5 , 24 ).
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-
    <Comment>DirectRegulation RASGRF1 --+&gt; Ras</Comment>
+
-
    <Comment>8626650 Here we report that mutations within the switch 2 domain of Ras (residues 62-69) inhibit activation of Ras by the mammalian GEFs, Sos1, and GRF/CDC25Mm.  
+
-
1447167 As a consequence, the CDC25Mm induces a rapid formation of the biologically active Ras.GTP complex.
+
--------------------------------------------------------------------------------
-
 
+
Source  Ariadne Pathways 
-
(Tissue: blood, CellType: b cell) Phosphorylation of RasGRP3 by PKC may be critical to modulate its association with Ras at the plasma membrane and the subsequent activation of the ERK MAPK cascade.
+
MedLine Reference  9473689:
-
 
+
Sentence  We propose a model in which inflammation-induced phosphorylation of CREB relieves CREB repression at the DYNCRE3 site, P-CREB binds to the c-Fos promoter, and Fos/Fra, P-CREB, and P-c-Jun interact at the DYNCRE3 site to activate prodynorphin gene transcription.
-
14749369 Furthermore, we have recently demonstrated that the ability of RasGRF1 to activate Ras is regulated by the Rho family GTPase Cdc42, by a mechanism that entails the translocation of RasGRF1 to the cell particulate fraction ( 3 , 4 ).
+
-
 
+
-
14676298 (CellType: b cell) This defective Ras activation is suppressed by the expression of RasGRP3 as a membrane-attached form, suggesting that phospholipase C-gamma2 regulates RasGRP3 localization and thereby Ras activation.
+
-
 
+
-
11500497 Our results suggest that mUBPy may play a role in controlling degradation of CDC25 Mm , thus regulating the level of this Ras-guanine nucleotide exchange factor.
+
-
 
+
-
15572660 (Tissue: endothelial) However, RasGRP2 is a Rap1 activator and not a Ras activator, whereas RasGRP3 is an activator of Ras and Rap1.
+
-
 
+
-
15213298 RasGRP3 activates both Ras and Rap1 (Yamashita et al., 2000 ), and RasGRP4 activates Ras (Reuther et al., 2002 ; Yang et al., 2002 ).
+
-
 
+
-
8717044 (CellLineName: COS-7) These results demonstrate a G-protein-coupled mechanism for Ras activation, mediated by p140 Ras-GRF.
+
-
 
+
-
8700529 (CellLineName: CHO) Transient expression of CDC25Mm in CHO cells activates Ras.  
+
 +
--------------------------------------------------------------------------------
 +
Journal Link  http://www.jimmunol.org/cgi/content/full/173/5/3557 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  15322221:10104 
 +
Sentence  The site that CREB binds to the c -fos promoter is a CRE centered on the ?57 nt. 
 +
Journal  J. Immunol 
 +
Journal Reference  v173 i5 p3557 
</Comment>
</Comment>
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-
     <Comment>DirectRegulation RASGRF1 --+&gt; RHOA</Comment>
+
     <Comment>Binding HTR1D ---- serotonin</Comment>
-
     <Comment>11058585 (CellType: neural) We recently isolated a putative GEF , termed p190RhoGEF that binds to RhoA and, when overexpressed in neuronal cells, induces cell rounding and inhibits neurite outgrowth.
+
     <Comment>[3H]5-HT binding, in the presence of pindolol (to block 5-HT1A and 5-HT1B receptors) and mesulergine (to block 5-HT1C receptors), was specific, saturable, reversible, and of high affinity. </Comment>
-
 
+
     <BiopaxRef>bd4</BiopaxRef>
-
12496377 (CellType: b cell, CellLineName: WEHI 231) CD40-induced cellular changes and the colocalization of p190RhoGEF with RhoA The enhanced p190RhoGEF expression after a 48-h CD40 stimulation was also shown by an indirect immunofluorescence for endogenous p190RhoGEF in WEHI 231 B cells (Fig. 2 A , 50–60% induction).
+
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   <Interaction GraphId="b8c07">
-
     <Comment>DirectRegulation RHOA --+&gt; MAP3K1,</Comment>
+
     <Comment>Binding HTR1E ---- serotonin</Comment>
-
     <Comment>15492006 (Tissue: endoderm) The recent observation that p115RhoGEF and RhoA can bind to MEKK, especially MEKK1 directly, might suggest an alternative pathway from Galpha13 to MEKK activation ( 55 , 59 ).
+
     <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand. </Comment>
-
 
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     <BiopaxRef>d9c</BiopaxRef>
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-
11315998 (CellLineName: AP) Moreover, SB203580, a specific inhibitor of p38 mitogen-activated protein kinase (MAPK), and PD-98059, a specific inhibitor of MAPK kinase (MEKK), also reduced IL-1alpha and RhoA expression in Ap cells.  
+
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</Comment>
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-
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+
   <Interaction GraphId="b8d8e">
-
     <Comment>DirectRegulation Ras --+&gt; MAP3K1,</Comment>
+
     <Comment>Binding GNAI3 ---- HTR1F</Comment>
-
     <Comment>7744823 The interaction between Ras and MEKK was GTP-stimulated as measured by the increased phosphorylation of KMMEK1 using GST-Ras (GTP S) beads incubated with recombinant MEKK .
+
     <Comment>Among the seven classes of serotonin (5-hydroxytryptamine, 5-HT) receptors which have been identified to date, the 5-HT(1) class is comprised of five receptor types, with the 5-HT(1A), 5-HT(1B) and 5-HT(1D) characterized by a high affinity for 5-carboxamido-tryptamine, the 5-HT(1E) and 5-HT(1F) characterized by a low affinity for this synthetic agonist, and all five having a nanomolar affinity for the endogenous indolamine ligand.  
-
 
+
-
7622446 So far, no direct interaction between Ras and MEKK1 has been observed, and it is not clear how it is activated by Ras.
+
-
 
+
-
11082445 Direct interaction between Ras and MEKK1 may result in the latter being stimulated (Russell et al., 1995 ).
+
-
 
+
-
8621725 (CellType: t cell, CellLineName: JURKAT) We recently demonstrated that MEKK activity can be stimulated by Ras and that MEKK1 physically binds to Ras in a GTP-dependent manner( 61 , 62 ) .  
+
</Comment>
</Comment>
-
     <BiopaxRef>f08</BiopaxRef>
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-
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-
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-
   <Interaction GraphId="a693b">
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-
     <Comment>DirectRegulation Ras --+&gt; BRAF</Comment>
+
     <Comment>DirectRegulation RASGRF1 --+&gt; RAP1A</Comment>
-
     <Comment>14984580 BRAF, a serine/threonine kinase, is a component of the retrovirus-associated sequence (RAS)-RAF-extracellular-regulated protein kinase (ERK)-MAP kinase signal transduction pathway mediating signals from RAS to ERK.  
+
     <Comment>10196191 In contrast, mutation of residue 70 does not affect the interaction of Cdc25 Mm with Rap1A and even increases the activity toward Ras(Q70L) almost 2-fold, indicating that residue 70 has an important role in the interaction with C3G but not as much with Cdc25 Mm .  
-
8887643 Unexpectedly, yeast two-hybrid binding analyses showed that although both Ras and TC21 could interact with the isolated Ras-binding domain of Raf-1, only Ras interacted with full-length Raf-1, A-Raf, or B-Raf.
+
15572660 (Tissue: endothelial) However, RasGRP2 is a Rap1 activator and not a Ras activator, whereas RasGRP3 is an activator of Ras and Rap1.  
-
 
+
-
11032810 In this report, we examined the potential phosphorylation sites in B-Raf responsible for Ras-induced activation.
+
-
 
+
-
11856330 However, clear inhibition of the interaction between Ras and B-Raf was not observed (Fig. 3C ).
+
-
 
+
-
11283246 In UT7-Mpl cells, Raf-1 but not B-Raf mediates the Ras-induced activation of Elk1.
+
-
 
+
-
8687465 (Organ: brain) These results suggest that there is a subtle structural difference in requirements for the interaction of Ras with Raf-1 and B-Raf.
+
-
 
+
-
8617731 (Organ: brain) In rat brain the association of MEK1 with Ras is dependent on B-Raf, not on Raf-1( 14 ) .
+
-
 
+
-
7744815 (Organ: brain) GTP-Ras directly interacts with B-Raf (13, 14) and c-Raf-1 ( 19 , 20 , 21 , 22 , 23 , 24 ) .
+
-
 
+
-
11696358 (Organ: kidney, CellLineName: 293) On the other hand, Ras-dependent extracellular signal-regulated kinase/mitogen-activated protein kinase kinase stimulator (a complex of B-Raf and 14-3-3) failed to activate Raf-1 in our cell-free system.
+
-
 
+
-
8622647 (CellLineName: NIH 3T3) B-Raf was not detectably tyrosine phosphorylated, membrane localized, or further activated upon Ras transformation, even though B-Raf has been shown to bind to Ras in vitro.  
+
 +
15213298 RasGRP3 activates both Ras and Rap1 (Yamashita et al., 2000 ), and RasGRP4 activates Ras (Reuther et al., 2002 ; Yang et al., 2002 ).
</Comment>
</Comment>
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     <BiopaxRef>e36</BiopaxRef>
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-
     <Comment>ProtModification PKC --+&gt; CREB1</Comment>
+
     <Comment>ProtModification MAPK3 --+&gt; MAPKAPK2</Comment>
-
     <Comment>15814901 Later, Xie and Rothstein showed that PKC phosphorylates CREB on Ser133 in B cells [ 41 ].  
+
     <Comment>MedLine Reference  10625698:1036 
 +
Sentence  Activated MAPK interacts with a number of downstream targets, including the p90 ribosomal S6 kinase (p90 Rsk ) ( 19 ) and MAPK-activated protein kinase-2 (MAPKAP-K2 ) ( 20 , 21 ), which are activated by ERK1/2 and p38 MAPK , respectively. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v275 i2 p1457 (2000) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/275/2/1457 
 +
Organ  ventricle 
 +
CellType  myocyte 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  7923353:0 
 +
Sentence  MAPK-activated protein kinase-2 (MAPKAP kinase-2) is activated in vitro by the p42 and p44 isoforms of MAPK (p42/p44MAPK).
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  8900202:1138 
 +
Sentence  MBP is an efficient substrate for ERK1 and ERK2, whereas GST-cJun (1-169) includes the activating phosphorylation sites Ser-63 and Ser-73, which have been shown to be phosphorylated by SAPK/JNK but not by ERK1, ERK2, or p38 HOG1 ( 3 ). 2 Similarly, hsp27 is an efficient substrate for MAPKAPK2, which in turn is predominantly activated by p38 HOG1, although MAPKAPK2 can also be phosphorylated in vitro by ERK1 and ERK2 ( 29 , 30 ). -- Fig. 2. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v271 i43 p27107 (1996) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/271/43/27107 
 +
CellLineName  Pam 212 
 +
Source  Ariadne Pathways 
-
15262987 In favor of this possibility, CREB has been shown to be phosphorylated by PKC in vitro ( 16 ).  
+
--------------------------------------------------------------------------------
-
 
+
MedLine Reference  7592979:1021 
-
11591753 Several pieces of evidence suggest that PKC can phosphorylate CREB directly.  
+
Sentence  In this article we use a recombinant glutathione S -transferase (GST)-MAPKAP kinase 2-fusion protein and various mutants to study the mechanism of activation of MAPKAP kinase 2 by p44 (ERK1) and p38/40 (RK) in vitro .
-
 
+
Journal  J. Biol. Chem 
-
11574420 Phosphorylation of CREB by PKC was reported to increase the binding of CREB to CRE in vitro and to stimulate CREB homodimerization or heterodimer complex formation with ATF-1, a transcription factor that shares many structural properties with CREB ( 37 , 38 , 39 , 40 ).  
+
Journal Reference  v270 i45 p27213 (1995)
 +
Journal Link  http://www.jbc.org/cgi/content/full/270/45/27213 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10753939:1120 
 +
Sentence  The ERK1 and ERK2 activator, MEK1 , has also been observed to activate MAPKAPK2 ( 58 ). 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v275 i15 p11284 (2000) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/275/15/11284 
 +
Source  Ariadne Pathways 
</Comment>
</Comment>
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-
     <Comment>ProtModification MAP3K1 --+&gt; MAP2K3</Comment>
+
     <Comment>G protein beta/gamma</Comment>
-
     <Comment>9006914 Activation of the JNK/p38 protein kinases involves a kinase cascade in which the upstream activator MAP kinase kinase kinase (MEKK) phosphorylates and activates MAP kinase kinase 3, 4, and 6 (MKK 3, 4 and 6), which in turn phosphorylate and activate JNK and p38 MAP kinases ( 34-37 ).  
+
    <Comment>Binding Gb/g ---- GNAO1</Comment>
 +
     <Comment>11124982 If the Getagamma subunits served as linkers, dialyzing Galpha o should have bound the Getagamma subunits, prevented their activation, and thus depolarized the cell.  
-
9065412 Although Mekk1 could phosphorylate Mek1, Mek2, Sek1, and MKK3, when it was expressed at physiological levels, only SAP kinase was markedly activated without Hog ( 13 ) or Erk ( 34 ) stimulation.  
+
(Tissue: plasma) Of interest, when mutations that disrupt interactions of Ga o with G��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩ? are combined with a G2A mutation to inhibit N -myristoylation, palmitoylation is no longer evident - even when plasma membrane targeting is apparently maintained ( Wang et al. , 1999b ).  
-
10358048 Each cascade consists of a three kinase module: a MAP kinase, a MAP kinase/ERK kinase (MEK ) that activates the MAP kinase, and a MEK kinase (MEKK ) that activates the MEK ( 3 ).
 
-
10644746 (CellLineName: 293T) Cotransfection of the cells with ASK-1 , a MEK kinase known to activate MEK3, resulted in increases in luciferase activity of up to 10-fold (data not shown).  
+
9065414 To analyze the interaction of Getagamma complex with Galpha o , 10 ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩg of Geta, 10 ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩg of Ggamma, and 10 ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩ��Ω��ΩΩ��Ω��ΩΩΩΩΩg of Galpha o DNAs were transfected.  
-
11304531 (CellLineName: HEK 293) For example, MEKK1 preferentially activates MKK3, MKK4, and MKK6 rather than MKK7 ( 39 ), whereas MEKK4 activates MKK3 and MKK6 rather than MKK4 ( 40 ).  
+
9346921 It has been shown that Galpha o forms a complex with Getagamma in HEK 293 cells ( 44 ).  
 +
-
11306453 In response to extracellular stimuli, MEKK1 is a strong activator of MKK4 and MKK7, and a weaker activator of MKK3 and MKK6 (Fig. 1 A ; Ref. 19 ).  
+
7761832 A peptide encoding residues 956 to 982 of adenylyl cyclase 2 specifically blocked G beta gamma stimulation of adenylyl cyclase 2, phospholipase C-beta 3, potassium channels, and beta-adrenergic receptor kinase as well as inhibition of calmodulin-stimulated adenylyl cyclases, but had no effect on interactions between G beta gamma and G alpha o.
 +
</Comment>
 +
    <BiopaxRef>ed0</BiopaxRef>
 +
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 +
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 +
    <Comment>Type your comment here</Comment>
 +
    <Comment>MedLine Reference  12842874:1221 
 +
Sentence  Several other kinases such as CKII, MAPK, PKC, and CaMK are known to phosphorylate CREB and thereby activate CREB-dependent transcription ( 25 , 26 , 29 , 30 , 49 , 56 - 59 ).
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v278 i40 p38860 (2003)
 +
Journal Link  http://www.jbc.org/cgi/content/full/278/40/38860 
 +
CellType  b cell 
 +
Source  Ariadne Pathways 
-
7797459 MEKK1 can activate MKK4, MKK3, MEK1, and MEK2( 27 , 46 , 47 ) , suggesting that MEKKs have a broader substrate specificity than MEKs.  
+
--------------------------------------------------------------------------------
 +
MedLine Reference  10931853:1209 
 +
Sentence  However, others have suggested that calcium/calmodulin-dependent kinases, Ras/mitogen-activated protein kinase, and protein kinase C can phosphorylate CREB at Ser 133 ( 47-49 ).
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v275 i43 p33365 (2000) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/275/43/33365 
 +
Source  Ariadne Pathways 
-
11956220 MEKK1 can also activate MEK3, which subsequently activates p38 MAPKs ( 30 , 31 ).  
+
--------------------------------------------------------------------------------
 +
MedLine Reference  11416000:1287 
 +
Sentence  CRE- binding protein (CREB) has been reported to be phosphorylated by MAP kinase-activated protein kinase, possibly through p70S6K, as well as cAMP kinase ( 35 , 36 ).
 +
Journal  Endocrinology 
 +
Journal Reference  v142 i7 p2811 (2001) 
 +
Journal Link  http://endo.endojournals.org/cgi/content/full/142/7/2811 
 +
Source  Ariadne Pathways 
-
11698415 (CellType: keratinocyte) MEKK1, in turn, activates MEK1, MEK3, and MEK7 ( 17 , 34 ).
+
--------------------------------------------------------------------------------
-
 
+
MedLine Reference  10098484:1177 
-
9639556 (CellType: keratinocyte) MEKK1, however, was found to activate additional MAPKKs, including Jun amino (N)-terminal kinase kinase 1(MKK4) [JNKK1(MKK4)] (DA?A�rijard et al. 1995 ; Lin et al. 1995 ), JNKK2(MKK7) (Wu et al. 1997 ), MKK3, and MKK6 (Stein et al. 1996 ).  
+
Sentence  However, the MEK inhibitor PD98059 was not able to modulate phosphorylation of CREB at a dose that fully inhibited the phosphorylation of MAP kinase (Fig. 6b ).
 +
Journal  Endocrinology 
 +
Journal Reference  v140 i4 p1525 (1999)
 +
Journal Link  http://endo.endojournals.org/cgi/content/full/140/4/1525 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10951185:1095 
 +
Sentence  This could occur via RSK2, a protein kinase activated by MAP kinases/ERKs, that phosphorylates CREB on its activator site serine 133 [ 43 ]. 
 +
Journal  Eur. J. Biochem 
 +
Journal Reference  v267 i17 p5280.html) (2000) 
 +
Journal Link  http://www.ejbiochem.org/cgi/content/full/267/17/5280.h 
 +
CellType  dendritic 
 +
Source  Ariadne Pathways 
</Comment>
</Comment>
-
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-
     <Comment>ProtModification MAP3K1 --+&gt; MAP2K6</Comment>
+
     <Comment>Binding GNAI2 ---- HTR1E</Comment>
-
     <Comment>9639556 MLK2 and MEKK1 also activated SKK2/MKK3 and SKK3/MKK6, the direct upstream activators of SAPK2a/p38.  
+
    <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.
 +
</Comment>
 +
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 +
    <Comment>PromoterBinding ELK1 --+&gt; FOS</Comment>
 +
     <Comment>--------------------------------------------------------------------------------
 +
Journal Link  http://www.jimmunol.org/cgi/content/full/167/2/827 
 +
CellType  t cell 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  11441089:1223 
 +
Sentence  Elk-1 is known to constitutively associate with serum response factor (SRF) homodimers at the serum response element (SRE) of the 5&amp;apos; c- fos gene DNA promoter/enhancer (reviewed by Cahill et al. in Ref. 28 ). 
 +
Journal  J. Immunol 
 +
Journal Reference  v167 i2 p827 (2001) 
-
9808624 MEKK1, however, was found to activate additional MAPKKs, including Jun amino (N)-terminal kinase kinase 1(MKK4) [JNKK1(MKK4)] (D?rijard et al. 1995 ; Lin et al. 1995 ), JNKK2(MKK7) (Wu et al. 1997 ), MKK3, and MKK6 (Stein et al. 1996 ).  
+
--------------------------------------------------------------------------------
 +
Journal Link  http://www.jbc.org/cgi/content/full/271/44/27366 
 +
CellType  t cell 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  8910314:1030 
 +
Sentence  In addition, JNKs up-regulate c-Fos expression by phosphorylation of the ternary complex factor, p62 TCF (Elk-1), which binds the c- fos promoter ( 23 , 25 ).
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v271 i44 p27366 (1996)
 +
--------------------------------------------------------------------------------
 +
Journal Link  http://www.jbc.org/cgi/content/full/275/21/16064 
 +
CellLineName  ags 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  10747974:1309 
 +
Sentence  Elk-1 binds the c- fos promoter together with the serum response factor ( SRF ) at the serum response element.
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v275 i21 p16064 (2000)
 +
--------------------------------------------------------------------------------
 +
Journal Link  http://www.jbc.org/cgi/content/full/277/43/40911 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  12145292:1036 
 +
Sentence  Subsequently, phosphorylated/activated Elk-1 binds the c- fos promoter and allows transcriptional activation of c- fos , an immediate early response gene ( 10 , 11 ).
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v277 i43 p40911 (2002) 
-
11306453 In response to extracellular stimuli, MEKK1 is a strong activator of MKK4 and MKK7, and a weaker activator of MKK3 and MKK6 (Fig. 1 A ; Ref. 19 ).  
+
--------------------------------------------------------------------------------
 +
Journal Link  http://www.jbc.org/cgi/content/full/273/27/16905 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  9642252:1220 
 +
Sentence  Elk-1 binds to a serum response element within the c- fos promoter region together with a serum response factor, inducing c-Fos expression ( 42 , 52 , 53 ).
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v273 i27 p16905 (1998)
 +
</Comment>
 +
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 +
    <Comment>DirectRegulation RHOA --+&gt; MAP3K1,</Comment>
 +
    <Comment>15492006 (Tissue: endoderm) The recent observation that p115RhoGEF and RhoA can bind to MEKK, especially MEKK1 directly, might suggest an alternative pathway from Galpha13 to MEKK activation ( 55 , 59 ).  
-
12960165 (CellLineName: RAW264.7) In addition, MEKK1 can stimulate the p38 MAPK through phosphorylation of MKK3 and MKK6 ( 37 ).
+
(CellLineName: AP)  
-
11574474 (CellLineName: 293) D-MEKK1 was found to phosphorylate MKK6 efficiently in vitro .  
+
11315998 (CellLineName: AP) Moreover, SB203580, a specific inhibitor of p38 mitogen-activated protein kinase (MAPK), and PD-98059, a specific inhibitor of MAPK kinase (MEKK), also reduced IL-1alpha and RhoA expression in Ap cells.  
</Comment>
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     <Comment>ProtModification MAP3K1 --+&gt; MAP2K2</Comment>
+
     <Comment>DirectRegulation CALCIUM --+&gt; RASGRF1</Comment>
-
     <Comment>9328344 (CellLineName: 293) MEK2 is Activated by MEKK1 and Ligands for Multiple Receptor Types in 293 Cells 293 cells transfected with HA-MEKK1 or empty vector were stimulated with EGF, carbachol, phorbol 12-myristate 13-acetate, and A1F 4 - as described.  
+
     <Comment>We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo in response to elevated calcium levels.
 +
</Comment>
 +
    <BiopaxRef>a17</BiopaxRef>
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 +
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 +
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 +
    <Comment>DirectRegulation CALCIUM --+&gt; RASGRP1,</Comment>
 +
    <Comment>CalDAG-GEFI and CalDAG-GEFII (identical to RasGRP) are novel, brain-enriched guanine nucleotide exchange factors (GEFs) that can be stimulated by calcium and diacylglycerol and that can activate small GTPases, including Ras and Rap1, molecules increasingly recognized as having signaling functions in neurons.
 +
</Comment>
 +
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 +
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 +
    <Comment>ProtModification MAP2K1 --+&gt; MAPK3</Comment>
 +
    <Comment>--------------------------------------------------------------------------------
 +
MedLine Reference  9927426:1014 
 +
Sentence  Both p42 and p44MAPK are activated by dual phosphorylation on a threonine and a tyrosine residue, achieved by the dual-specificity kinase MKK1/2. 
 +
Journal  EMBO 
 +
Journal Reference  v18 i3 p664 (1999) 
 +
Journal Link  http://embojournal.npgjournals.com/cgi/content/full/18/3/664 
 +
CellType  fibroblast 
 +
CellLineName  PC 12
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12393899:1257 
 +
Sentence  Furthermore, expression of a constitutively active MKK1, which directly activated ERK1/2, suppressed cortical neuron apoptosis induced by expression of recombinant wild-type GSK3eta or the GSK3eta(S9A) mutant.
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v277 i51 p49577 (2002) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/277/51/49577 
 +
Tissue  cortex 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10958792:5 
 +
Sentence  In the ovarian carcinoma cell line A2780, inhibition of ERK1/2 activation with the mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 resulted in decreased p53 protein half-life and diminished accumulation of p53 protein during exposure to cisplatin. 
 +
CellLineName  A2780 
 +
Source  Ariadne Pathways 
-
12242299 Conceivably, the two compounds may act through distinct mechanisms, in which U-0126 directly suppresses MKK1/2 activity, whereas PD-98059 suppresses MKK1/2 phosphorylation and activation by upstream kinases such as Raf-1 or MEK kinase-1 ( 5 , 17 ).  
+
--------------------------------------------------------------------------------
 +
MedLine Reference  9159118:3 
 +
Sentence  Inhibiting activation of ERK1 and ERK2 with the MEK1/2 inhibitor PD98059 has no effect on insulin secretion, indicating that ERK activity is not necessary for secretion under these conditions.
 +
Source  Ariadne Pathways 
-
8969228 (CellType: neutrophil) Our data suggest that in human neutrophils both MEK1 and MEK2 are activated by MEKK and that PI 3-kinase may modulate MEKK activation and that of its two downstream components (MEK and MAPK).
+
--------------------------------------------------------------------------------
 +
MedLine Reference  11673351:5 
 +
CellType  cardiomyocyte 
 +
Source  Ariadne Pathways 
-
11588191 (CellLineName: PC 12) In parallel experiments, we verified that c-MEKK1 led to phosphorylation of MAP kinase through a mechanism involving MEK-1/2 activation by examining effects of the MEK-1/2 inhibitor U0126.
+
--------------------------------------------------------------------------------
-
 
+
MedLine Reference  10711350:
-
7797459 MEKK1 can activate MKK4, MKK3, MEK1, and MEK2( 27 , 46 , 47 ) , suggesting that MEKKs have a broader substrate specificity than MEKs.
+
Sentence  PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially. 6. 
-
 
+
CellType macrophage 
-
9162092 Additionally, the catalytic domain of MEKK1 activated MEK1 and MEK2 in vitro and interacted with MEK in the yeast two-hybrid system.
+
CellLineName RAW264.
-
 
+
Source  Ariadne Pathways 
-
8940180 Furthermore, expression of MEKK1 in mammalian cells led to the constitutive activation of Mek1 and Mek2 but not of Erk2 ( 34 ).  
+
-
 
+
-
10918063 (Tissue: squamous, CellType: keratinocyte, CellLineName: TBE) MEKK1 phosphorylates MKK1/2, which then activates two downstream kinases, ERK1 and ERK2, to stimulate the binding of transcription factors to regulate target gene expression ( 68 ).  
+
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11496823:2 
 +
Sentence  PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed the thapsigargin-induced histamine production, the increase in HDC mRNA level and 74-kDa HDC protein expression. 
 +
CellType  macrophage 
 +
CellLineName  RAW264.7 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  9235901:1031 
 +
Sentence  In the mammalian Erk1/2 pathway, the proximal kinases Raf-1 and B-Raf phosphorylate and activate the dual function threonine/tyrosine kinases MAP/Erk kinases 1 and 2, which in turn phosphorylate Erk1/2. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v272 i31 p19125 (1997) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/272/31/19125 
 +
Organ  heart 
 +
CellType  myocyte 
 +
CellLineName  AR 
 +
Source  Ariadne Pathways 
</Comment>
</Comment>
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     <Comment>ProtModification BRAF --+&gt; MAP2K2,</Comment>
+
     <Comment>DirectRegulation 1,2-Diacetin --+&gt; PKC</Comment>
-
     <Comment>12801936 (Organ: pituitar, Tissue: epithelia) ERKs are activated by the mitogen-activated protein kinase kinases, MEK1 and MEK2, which are activated by the MEK kinases, Raf-1, A-Raf, and B-Raf.
+
     <Comment>The "conventional" PKC isoforms ( , ?1, ?II, and ) are regulated by DAG, which binds the C1 domain, and by Ca2+, which binds the C2 domain.  
-
 
+
-
10783132 (Organ: lung, Tissue: epithelia) Raf-1 and B-Raf are serine/threonine-protein kinases that selectively phosphorylate and activate MEK1 and MEK2 ( 22 ).
+
-
 
+
-
8621389 Raf-1 and B-Raf are serine/threonine-protein kinases that selectively phosphorylate and activate MEK 1 and MEK 2( 14 , 15 , 16 , 17 ) .
+
-
 
+
-
12351703 Next, actions of the D2 receptor on c-Raf and B-Raf, which phosphorylate MEK1/2, were examined (Fig. 10 ).
+
-
 
+
-
8668348 We show that, consequently, B-Raf interacts with MEK-1 and MEK-2 with a better affinity than does c-Raf-1, thus strengthening the notion that B-Raf is a stronger MEK activator than c-Raf-l.
+
-
 
+
-
15153095 (CellType: neural) In addition, MEK1/2 can be activated by B-Raf, a neuron-enriched isoform of Raf, which is in turn activated by a cAMP-responsive Ras homologue called Rap-1 [ 41 ].
+
-
 
+
-
9733801 (CellLineName: COS I) A , quantitative analysis of the interaction of Raf-1 and B-Raf with MEK-1 and MEK-2 in the yeast two-hybrid system.
+
-
 
+
-
12738761 Next, actions of the D2 receptor on c-Raf and B-Raf, which phosphorylate MEK1/2, were examined (Fig. 10 ).  
+
</Comment>
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-
     <Comment>ProtModification BRAF --+&gt; MAP2K1,</Comment>
+
     <Comment>ProtModification MAP2K6 --+&gt; MAPK14,</Comment>
-
     <Comment>12167697 Reactions were immunoblotted as indicated. (B) The reactions were identical to those for panel A, except that recombinant WT-MEK1 activated by recombinant B-Raf in vitro was used to phosphorylate the immunoprecipitated ERKs.  
+
     <Comment>12746452 Several upstream kinases have been implicated in the activation of the p38 MAPK and JNK 1/2 including apoptosis signaling kinase-1 which appears to activate both p38 MAPK and JNK 1/2, MKK 3/6 which activates p38 MAPK, and MKK 4/7 which activates JNK 1/2 ( 23 ).  
-
12351703 V., Calleja V., Scimeca J.-C., Filloux C., Calothy G. and Van Obberghen E. (1995) Regulation of the MAP kinases cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP.  
+
12649265 Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38??2 MAPK inhibited interleukin-1????induced p38 MAPK activation, COX-2 gene expression, and PGE2 release.  
-
15153095 In addition, MEK1/2 can be activated by B-Raf, a neuron-enriched isoform of Raf, which is in turn activated by a cAMP-responsive Ras homologue called Rap-1 [ 41 ].  
+
10942386 In contrast, neither dominant negative MKK6 nor SB203580, which specifically inhibit p38 MAP kinase activation, abrogated the MNNG-induced effect.  
-
14570902 The activated Ras and Rap1 stimulate sequential activation of Raf serine/threonine kinases C-Raf and B-Raf, respectively, which in turn activate MEK1/ERKs.  
+
12600999 ERK is activated by MEK1 and MEK2, whereas p38 kinase is activated by MKK3 and MKK6, and JNK is activated by MKK4 ( 24-28 ).  
-
7559496 We also showed that B-Raf interacts in vivo with Mek-1 and phosphorylates this protein on both serine 218 and 222( 25 ) .  
+
12670941 Among them, MKK6 and MKK3 activate p38 MAPK.  
-
15572664 Activated B-Raf activates MEK1, which in turn phosphorylates and activates ERK1/2 for a sustained period.  
+
11245462 This pathway is stimulated by environmental and chemical stress as well as by exposure to cytokines, and it appears to play a role in the induction of apoptosis (10 , 11) . p38 MAPK is activated by hyperosmolarity and environmental stress and regulates pro- or anti-apoptotic effects in a stimulus and cell-type specific manner (12 , 13) . p38 MAPK is phosphorylated by either MKK3 (14) or MKK6 (15 , 16) .  
-
8668348 We show that, consequently, B-Raf interacts with MEK-1 and MEK-2 with a better affinity than does c-Raf-1, thus strengthening the notion that B-Raf is a stronger MEK activator than c-Raf-l.  
+
11732999 (CellType: chondrocyte) On the other hand, p38 MAPK is known to be a stress signal transducer, and phosphorylation of p38 MAPK in chondrocytes by EGF [ 25 ], PTH [ 41 ], and GDF-5 [ 42 ] regulates differentiation of chondrocytes. p38 MAPK is phosphorylated by MKK3, and MKK6 [ 45 ], and Atf-2 is one of the transcription factors downstream of p38 MAPK [ 31 ].  
-
7731720 However, there has been no evidence for a direct interaction between B-Raf and Mek-1.  
+
10716930 Thus, MKK3 requires a docking domain for efficient dual phosphorylation of p38alpha, but MKK6 is able to phosphorylate p38alpha on both threonine and tyrosine in the absence of a docking domain.  
-
12218141 (CellType: neutrophil) This is consistent with other findings that C5a causes the activation of Raf-1 and B-Raf, which are upstream stimulators of MEK-1 in human neutrophils, with a peak of activation at 5 min, followed by suppressed activation thereafter ( 38 ).  
+
11500363 (CellLineName: HeLa) MKK4 and MKK6 are both known to phosphorylate stress-activated protein kinase 2a (SAPK2a, also called p38).  
</Comment>
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-
     <Comment>ProtModification MAP2K3 --+&gt; MAPK14,</Comment>
+
     <Comment>MolTransport ITPR1 --+&gt; CALCIUM,</Comment>
-
     <Comment>11245462 This pathway is stimulated by environmental and chemical stress as well as by exposure to cytokines, and it appears to play a role in the induction of apoptosis (10 , 11) . p38 MAPK is activated by hyperosmolarity and environmental stress and regulates pro- or anti-apoptotic effects in a stimulus and cell-type specific manner (12 , 13) . p38 MAPK is phosphorylated by either MKK3 (14) or MKK6 (15 , 16) .  
+
     <Comment>8571671 The molecular basis of the complex Ca2+ signals is the regenerative character of the inositol trisphosphate receptor (InsP3R) responsible for the release of Ca2+ from intracellular stores.  
-
8939929 B , graphical representation of p38 hog and SAPK activation in each cell line and in vector transfected G418-resistant control cells. [View Larger Version of this Image (39K GIF file)] MKK3-AL and MKK6-AL Expression Impair the Activation of p38 hog But Not SAPK MKK3 and MKK6 can phosphorylate p38 hog in vitro and have been proposed as potential physiologic p38 hog activators ( 18 , 19 , 20 ).  
+
8765993 A Ca2+-mediated conformational change of the InsP3R is most likely the key feature of the mechanism for quantal Ca2+ release, but the exact mode of operation remains unclear.  
-
11732999 (CellType: chondrocyte) On the other hand, p38 MAPK is known to be a stress signal transducer, and phosphorylation of p38 MAPK in chondrocytes by EGF [ 25 ], PTH [ 41 ], and GDF-5 [ 42 ] regulates differentiation of chondrocytes. p38 MAPK is phosphorylated by MKK3, and MKK6 [ 45 ], and Atf-2 is one of the transcription factors downstream of p38 MAPK [ 31 ].  
+
9675184 The InsP3R channels release Ca2+ from intracellular compartments to generate localized Ca2+ transients that govern a myriad of cellular signaling phenomena (Berridge, 1993. Nature. 361:315-325; Joseph, 1996. Cell Signal. 8:1-7; Kume et al., 1997. Science. 278:1940-1943; Berridge, 1997. Nature. 368:759-760). express multiple InsP3R isoforms, but only the function of the single type 1 InsP3R channel is known.  
-
10716930 Since MKK3 does not bind to p38alpha or p38eta2, the selectivity of MKK3 in activating p38alpha MAPK is not caused by a difference in docking interactions of MKK3 with p38alpha and p38eta2.  
+
15201137 (Tissue: skeletal) Agonist-induced increase in gene expression and calcium release were blocked by the InsP(3)R inhibitors 2-aminoethoxydiphenyl borate and xestospongin C.  
-
11560921 SEK-1 and MKK-3/6 are known to phosphorylate p38 MAPK and SAPK/JNK, respectively ( 41-45 ); thus, we theorize that alpha-synuclein affects the phosphorylation of MAPKs by MAPKKs.  
+
15677321 Addition of native GAPDH and NAD(+) to WT IP(3)R stimulates calcium release, whereas no stimulation occurs with C992S/995S IP(3)R that cannot bind GAPDH.  
-
12589052 (CellLineName: COS I) Expression of Smad7 facilitates the interaction between MKK3 and p38 MAP kinase.  
+
9607940 The inositol (1,4,5)-trisphosphate receptor (InsP3R) mediates Ca2+ release from intracellular stores in response to generation of second messenger InsP3.  
-
10593906 Both MKK3 and MKK6 are upstream kinases that can activate and phosphorylate p38 MAPK ( 25 , 26 ).  
+
7533300 (Tissue: skeletal muscle) Disrupting the IP3R-FKBP12 interaction increases Ca2+ flux through IP3R, an effect that is reversed by added FKBP12.  
-
9430721 These data demonstrate that MKK3 and MKK6 differentially phosphorylate p38 MAP kinase isoforms.  
+
9831561 The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) acts as a Ca2+ release channel on internal Ca2+ stores.  
-
9379049 (Tissue: marrow, CellType: macrophage)  
+
10096607 Inositol 1,4,5-trisphosphate receptors (IP3R) are mediators of second messenger-induced intracellular calcium release.
-
MKK3 phosphorylates an unspecified isoform of p38. This interaction was modeled on a demonstrated interaction between human MKK3 and p38 from an unspecified species
+
12491767 IP3receptor (IP3R) works as an IP3 induced Ca2+ release channel and requires IP3 and Ca2+ as coagoinist.
-
8622669 (Organ: heart, Tissue: smooth muscle, CellType: cardiomyocyte, CellLineName: MB-231) In contrast, MKK3, MKK4, and MKK6 contribute to p38 MAPK activation caused by UV radiation.  
+
</Comment>
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 +
    <Comment>Binding GNAI3 ---- HTR1D</Comment>
 +
    <Comment>Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor
 +
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 +
    <Comment>ProtModification MAP3K1 --+&gt; MAP2K6</Comment>
 +
    <Comment>9639556 MLK2 and MEKK1 also activated SKK2/MKK3 and SKK3/MKK6, the direct upstream activators of SAPK2a/p38.  
 +
9808624 MEKK1, however, was found to activate additional MAPKKs, including Jun amino (N)-terminal kinase kinase 1(MKK4) [JNKK1(MKK4)] (D?rijard et al. 1995 ; Lin et al. 1995 ), JNKK2(MKK7) (Wu et al. 1997 ), MKK3, and MKK6 (Stein et al. 1996 ).
 +
 +
11306453 In response to extracellular stimuli, MEKK1 is a strong activator of MKK4 and MKK7, and a weaker activator of MKK3 and MKK6 (Fig. 1 A ; Ref. 19 ).
 +
 +
12960165 (CellLineName: RAW264.7) In addition, MEKK1 can stimulate the p38 MAPK through phosphorylation of MKK3 and MKK6 ( 37 ).
 +
 +
11574474 (CellLineName: 293) D-MEKK1 was found to phosphorylate MKK6 efficiently in vitro .
</Comment>
</Comment>
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     <BiopaxRef>ee1</BiopaxRef>
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     <BiopaxRef>cda</BiopaxRef>
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     <BiopaxRef>dee</BiopaxRef>
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    <BiopaxRef>a52</BiopaxRef>
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    <BiopaxRef>e6e</BiopaxRef>
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    <BiopaxRef>eca</BiopaxRef>
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     <Comment>ProtModification MAP2K6 --+&gt; MAPK14,</Comment>
+
     <Comment>Binding ELK4 ---- SRF</Comment>
-
     <Comment>12746452 Several upstream kinases have been implicated in the activation of the p38 MAPK and JNK 1/2 including apoptosis signaling kinase-1 which appears to activate both p38 MAPK and JNK 1/2, MKK 3/6 which activates p38 MAPK, and MKK 4/7 which activates JNK 1/2 ( 23 ).  
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    <Comment>ProtModification PKC --+&gt; CREB1</Comment>
 +
    <Comment>15814901 Later, Xie and Rothstein showed that PKC phosphorylates CREB on Ser133 in B cells [ 41 ].  
-
12649265 Infecting cardiomyocytes with adenoviruses that encode mutant, phosphorylation-resistant MKK6 or p38??2 MAPK inhibited interleukin-1????induced p38 MAPK activation, COX-2 gene expression, and PGE2 release.  
+
15262987 In favor of this possibility, CREB has been shown to be phosphorylated by PKC in vitro ( 16 ).  
-
10942386 In contrast, neither dominant negative MKK6 nor SB203580, which specifically inhibit p38 MAP kinase activation, abrogated the MNNG-induced effect.  
+
11591753 Several pieces of evidence suggest that PKC can phosphorylate CREB directly.  
-
12600999 ERK is activated by MEK1 and MEK2, whereas p38 kinase is activated by MKK3 and MKK6, and JNK is activated by MKK4 ( 24-28 ).  
+
11574420 Phosphorylation of CREB by PKC was reported to increase the binding of CREB to CRE in vitro and to stimulate CREB homodimerization or heterodimer complex formation with ATF-1, a transcription factor that shares many structural properties with CREB ( 37 , 38 , 39 , 40 ).  
-
12670941 Among them, MKK6 and MKK3 activate p38 MAPK.  
+
</Comment>
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 +
    <Comment>Regulation PtdIns3P --+&gt; PDPK1</Comment>
 +
    <Comment>Phosphorylation of Akt at threonine 308 is catalyzed by the ubiquitously expressed and constitutively activated phosphatidylinositol 3,4,5-triphosphate-dependent protein kinase-1 (PDK-1) ( 34 , 35 ).
 +
</Comment>
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  </Interaction>
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  <Interaction GraphId="ceac4">
 +
    <Comment>ProtModification RPS6KA5 --+&gt; CREB1</Comment>
 +
    <Comment>MedLine Reference  12414794:1133 
 +
Sentence  MSK1 has been shown to phosphorylate CREB and to be activated by EGF , as well as ERK1/2 and p38 MAPKs ( 27 ). 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v277 i52 p50550 (2002) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/277/52/50550 
 +
CellLineName  HeLa 
 +
Source  Ariadne Pathways 
-
11245462 This pathway is stimulated by environmental and chemical stress as well as by exposure to cytokines, and it appears to play a role in the induction of apoptosis (10 , 11) . p38 MAPK is activated by hyperosmolarity and environmental stress and regulates pro- or anti-apoptotic effects in a stimulus and cell-type specific manner (12 , 13) . p38 MAPK is phosphorylated by either MKK3 (14) or MKK6 (15 , 16) .  
+
--------------------------------------------------------------------------------
 +
MedLine Reference  12896977:1312 
 +
Sentence  It is interesting to note that H89 is also a potent inhibitor of protein kinase A (PKA) and that both MSK1 and PKA can phosphorylate CREB.
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v278 i42 p41034 (2003)
 +
Journal Link  http://www.jbc.org/cgi/content/full/278/42/41034 
 +
CellType  lymphocyte 
 +
Source  Ariadne Pathways 
-
11732999 (CellType: chondrocyte) On the other hand, p38 MAPK is known to be a stress signal transducer, and phosphorylation of p38 MAPK in chondrocytes by EGF [ 25 ], PTH [ 41 ], and GDF-5 [ 42 ] regulates differentiation of chondrocytes. p38 MAPK is phosphorylated by MKK3, and MKK6 [ 45 ], and Atf-2 is one of the transcription factors downstream of p38 MAPK [ 31 ].  
+
--------------------------------------------------------------------------------
 +
MedLine Reference  9687510:1176 
 +
Sentence  MSK1 phosphorylates CREB at Ser133. ( A ) Comparison of the substrate specificities of MSK1, MAPKAP-K1a and MAPKAP-K1b towards the indicated peptides and CREB. 
 +
Journal  EMBO 
 +
Journal Reference  v17 i15 p4426 (1998) 
 +
Journal Link  http://embojournal.npgjournals.com/cgi/content/full/17/15/4426 
 +
Source  Ariadne Pathways 
-
10716930 Thus, MKK3 requires a docking domain for efficient dual phosphorylation of p38alpha, but MKK6 is able to phosphorylate p38alpha on both threonine and tyrosine in the absence of a docking domain.  
+
--------------------------------------------------------------------------------
-
 
+
MedLine Reference  11907026:1243 
-
11500363 (CellLineName: HeLa) MKK4 and MKK6 are both known to phosphorylate stress-activated protein kinase 2a (SAPK2a, also called p38).  
+
Sentence  MSK-1 phosphorylates CREB in response to FGF or NGF in PC12 cells.
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v277 i21 p18710 (2002)
 +
Journal Link  http://www.jbc.org/cgi/content/full/277/21/18710 
 +
CellLineName  PC 12 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11701463:1152 
 +
Sentence  Activated MSK1 phosphorylates CREB at Ser133. 
 +
Journal  ATVB 
 +
Journal Reference  v21 i11 p1764 (2001) 
 +
Journal Link  http://atvb.ahajournals.org/cgi/content/full/21/11/1764 
 +
Source  Ariadne Pathways 
</Comment>
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 +
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 +
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 +
    <Comment>Binding GNAI1 ---- HTR1E</Comment>
 +
    <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.
 +
</Comment>
 +
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   <Interaction GraphId="d0a0d">
-
     <Comment>ProtModification MAP2K1 --+&gt; MAPK1</Comment>
+
     <Comment>DirectRegulation 1,2-Diacetin --+&gt; RASGRF1</Comment>
-
     <Comment>--------------------------------------------------------------------------------
+
     <Comment>RasGRP3 localization and activity is regulated by DAG, and this interaction is mimicked by the phorbol ester PMA.  
-
MedLine Reference  10428835:1222 
+
</Comment>
-
Sentence  PD98059 is a specific inhibitor for MKK1 and -2 ( 56 ), upstream kinases that phosphorylate and activate ERK ( 15 , 57 ).
+
    <BiopaxRef>dfa</BiopaxRef>
-
Journal  J. Biol. Chem 
+
    <Graphics ZOrder="12288" LineThickness="1.0">
-
Journal Reference  v274 i32 p22569 (1999) 
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Journal Link  http://www.jbc.org/cgi/content/full/274/32/22569 
+
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-
Tissue  cortex 
+
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-
CellType  neural 
+
    <Xref Database="" ID="" />
-
CellLineName  DIV 
+
  </Interaction>
-
Source  Ariadne Pathways 
+
  <Interaction GraphId="d60c1">
-
--------------------------------------------------------------------------------
+
    <Comment>DirectRegulation CALCIUM --+&gt; PKC,</Comment>
-
MedLine Reference  12529254:1190 
+
    <Comment>10713965 PDBu-induced activation of PKC promotes the priming of secretory granules, thereby enhancing the efficacy for Ca2+ to trigger fusion/exocytosis.  
-
Sentence  The present study provides direct evidence that the P2X7-R can mediate ERK1/2 activation through a cellular pathway that is dependent on intracellular and extracellular Ca2+, Pyk2, c-Src, PI 3-K, and MEK1/2.
+
-
Journal  Cell Phys 
+
-
Journal Reference  v284 i2 pC571 (2003) 
+
-
Journal Link  http://ajpcell.physiology.org/cgi/content/full/284/2/C571 
+
-
CellType  macrophage 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
-
MedLine Reference  10827000:1180 
+
-
Sentence  MEK1 activity was assayed in muscle protein by measuring the ability of MEK1 immune complexes to phosphorylate a recombinant kinase-inactive MAPK (p42MAPK).
+
-
Journal  Endocrin. Metabol 
+
-
Journal Reference  v278 i6 pE992 (2000) 
+
-
Journal Link  http://ajpendo.physiology.org/cgi/content/full/278/6/E992 
+
-
Tissue  muscle 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
-
MedLine Reference  12746434:1159 
+
-
Sentence  These activation kinetic data are consistent with the fact that ERK1/2 is specifically activated by MEK1/2.
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v278 i31 p29000 (2003) 
+
-
Journal Link  http://www.jbc.org/cgi/content/full/278/31/29000 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
8429046 It appears, therefore, that the binding of Ca2+ to PKC requires a complex tertiary structure in the regulatory domain.  
-
MedLine Reference  9207092:1125 
+
-
Sentence  Control experiments demonstrated that ERK2 and p38alpha were activated by their cognate MAP kinase kinases, MKK1 and MKK6 (data not shown). 
+
-
Journal  PNAS 
+
-
Journal Reference  v94 i14 p7337 (1997) 
+
-
Journal Link  http://www.pnas.org/cgi/content/full/94/14/7337 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
1313322 (Tissue: articular cartilage, CellType: chondrocyte) The activity of various subspecies of protein kinase C (PKC) in chondrocytes derived from rodent costal cartilage and bovine articular cartilage has been determined and the role of PKC in GAG synthesis as well as the possible interactions of PKC with calcium- or cyclic AMP (cAMP)-dependent systems in the synthesis of GAG.  
-
MedLine Reference  10636870:1150 
+
-
Sentence  MEK1/2 inhibition prevents H 2 O 2 -mediated activation of ERK1/2 to a greater extent than activation of p90RSK. 
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v275 i3 p1739 (2000)
+
-
Journal Link  http://www.jbc.org/cgi/content/full/275/3/1739 
+
-
CellLineName  JURKAT 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
10325235 (CellType: cardiomyocyte) Phorbol ester-sensitive PKC isoforms were detected at very low levels in caveolae fractions prepared from unstimulated cardiomyocytes; phorbol 12-myristate 13-acetate (PMA) (but not 4alpha-PMA, which does not activate PKC) recruited calcium-sensitive PKCalpha and novel PKCdelta and PKCepsilon to this compartment.  
-
MedLine Reference  11303030:1103 
+
-
Sentence  The closely related mammalian kinases, ERK1 and ERK2 (also called p44 and p42), are activated by the MEK1/2 kinases in response to mitogenic signals. 
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v276 i24 p20805 (2001) 
+
-
Journal Link  http://www.jbc.org/cgi/content/full/276/24/20805 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
9725212 (CellType: t cell) Since cyclosporin does not have any effect on cytosolic Ca 2+ levels and thus does not interfere with the interaction between PKC and Ca 2+ , we tested the effect of an inhibitor of intracellular Ca 2+ redistribution, TMB-8 ( 36 ), on TCR cross-linking-induced AICD.
-
MedLine Reference  11571230:1117 
+
 
-
Sentence  Assessment of VES-induced differentiation after blockage of ERK1/2 activation by MEK1 using the chemical inhibitor PD 98059.
+
10751227 (Tissue: mesangia) DAG can directly activate classical types of PKC by interacting with its lipid-binding domain, and IP3 can indirectly activate PKC by increasing intracellular Ca2+, which interacts with the PKC Ca2+-binding domain.
-
Journal  Cell Growth and Diff 
+
 
-
Journal Reference  v12 i9 p471 (2001)
+
11342594 Synaptotagmins are transmembrane proteins with a short NH2-terminal ectodomain, a single transmembrane region, and two highly conserved, independently folding Ca2+-binding C2 domains (C2A and C2B) homologous to the C2 regulatory region of protein kinase C.
-
Journal Link  http://cgd.aacrjournals.org/cgi/content/full/12/9/471 
+
 
-
Source  Ariadne Pathways 
+
7836388 At odds with the concept of calcium modulation of lipid binding, these authors considered phospholipids as modulators for the binding of calcium to PKC( 31 , 34 ) .  
 +
 
 +
9852158 The four inhibitors of PKC all accelerated the breakdown of the F-actin network observed after 5 min (Fig. 6 D ) and 30 min (Fig. 6 E ) in 0 Ca 2+ .  
 +
 
 +
9218480 These data reveal that the negative charge on the carboxyl terminus of protein kinase C contributes to the interaction of protein kinase C with Ca 2+ .
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  12226077:1214 
 
-
Sentence  Expression of dominant negative MEK1 significantly attenuates the bFGF-induced phosphorylation of ERK1/2 (Fig. 3 C , lane 4 on the bottom panel ). 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v277 i46 p44417 (2002) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/277/46/44417 
 
-
Source  Ariadne Pathways 
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  12960148:1141 
 
-
Sentence  Furthermore, S100A1-mediated activation of ERK 1/2 could be prevented by preincubation with PD98095 (2-10 � M ) ( Fig. 6 B ), a specific inhibitor of MEK1 ( 26 , 27 ). 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v278 i48 p48404 (2003) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/278/48/48404 
 
-
Source  Ariadne Pathways 
 
</Comment>
</Comment>
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-
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-
     <Comment>ProtModification MAP2K1 --+&gt; MAPK3</Comment>
+
     <Comment>ProtModification MAP2K3 --+&gt; MAPK14,</Comment>
-
     <Comment>--------------------------------------------------------------------------------
+
     <Comment>11245462 This pathway is stimulated by environmental and chemical stress as well as by exposure to cytokines, and it appears to play a role in the induction of apoptosis (10 , 11) . p38 MAPK is activated by hyperosmolarity and environmental stress and regulates pro- or anti-apoptotic effects in a stimulus and cell-type specific manner (12 , 13) . p38 MAPK is phosphorylated by either MKK3 (14) or MKK6 (15 , 16) .  
-
MedLine Reference  9927426:1014 
+
-
Sentence  Both p42 and p44MAPK are activated by dual phosphorylation on a threonine and a tyrosine residue, achieved by the dual-specificity kinase MKK1/2. 
+
-
Journal  EMBO 
+
-
Journal Reference  v18 i3 p664 (1999)
+
-
Journal Link  http://embojournal.npgjournals.com/cgi/content/full/18/3/664 
+
-
CellType  fibroblast 
+
-
CellLineName  PC 12 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
-
MedLine Reference  12393899:1257 
+
-
Sentence  Furthermore, expression of a constitutively active MKK1, which directly activated ERK1/2, suppressed cortical neuron apoptosis induced by expression of recombinant wild-type GSK3eta or the GSK3eta(S9A) mutant.
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v277 i51 p49577 (2002)
+
-
Journal Link  http://www.jbc.org/cgi/content/full/277/51/49577 
+
-
Tissue  cortex 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
-
MedLine Reference  10958792:5 
+
-
Sentence  In the ovarian carcinoma cell line A2780, inhibition of ERK1/2 activation with the mitogen-activated protein kinase/ERK kinase 1 (MEK1) inhibitor PD98059 resulted in decreased p53 protein half-life and diminished accumulation of p53 protein during exposure to cisplatin.
+
-
CellLineName  A2780 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
8939929 B , graphical representation of p38 hog and SAPK activation in each cell line and in vector transfected G418-resistant control cells. [View Larger Version of this Image (39K GIF file)] MKK3-AL and MKK6-AL Expression Impair the Activation of p38 hog But Not SAPK MKK3 and MKK6 can phosphorylate p38 hog in vitro and have been proposed as potential physiologic p38 hog activators ( 18 , 19 , 20 ).  
-
MedLine Reference  9159118:3 
+
-
Sentence  Inhibiting activation of ERK1 and ERK2 with the MEK1/2 inhibitor PD98059 has no effect on insulin secretion, indicating that ERK activity is not necessary for secretion under these conditions.
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
11732999 (CellType: chondrocyte) On the other hand, p38 MAPK is known to be a stress signal transducer, and phosphorylation of p38 MAPK in chondrocytes by EGF [ 25 ], PTH [ 41 ], and GDF-5 [ 42 ] regulates differentiation of chondrocytes. p38 MAPK is phosphorylated by MKK3, and MKK6 [ 45 ], and Atf-2 is one of the transcription factors downstream of p38 MAPK [ 31 ].
-
MedLine Reference  11673351:5 
+
-
CellType  cardiomyocyte 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
10716930 Since MKK3 does not bind to p38alpha or p38eta2, the selectivity of MKK3 in activating p38alpha MAPK is not caused by a difference in docking interactions of MKK3 with p38alpha and p38eta2.
-
MedLine Reference  10711350:4 
+
 
-
Sentence  PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)- and TPA (30 nM)-induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially. 6.
+
11560921 SEK-1 and MKK-3/6 are known to phosphorylate p38 MAPK and SAPK/JNK, respectively ( 41-45 ); thus, we theorize that alpha-synuclein affects the phosphorylation of MAPKs by MAPKKs.
-
CellType macrophage
+
 
-
CellLineName RAW264.
+
12589052 (CellLineName: COS I) Expression of Smad7 facilitates the interaction between MKK3 and p38 MAP kinase.
-
Source  Ariadne Pathways 
+
 
 +
10593906 Both MKK3 and MKK6 are upstream kinases that can activate and phosphorylate p38 MAPK ( 25 , 26 ).  
 +
 
 +
9430721 These data demonstrate that MKK3 and MKK6 differentially phosphorylate p38 MAP kinase isoforms.  
 +
 
 +
9379049 (Tissue: marrow, CellType: macrophage)
 +
 
 +
MKK3 phosphorylates an unspecified isoform of p38. This interaction was modeled on a demonstrated interaction between human MKK3 and p38 from an unspecified species
 +
 
 +
8622669 (Organ: heart, Tissue: smooth muscle, CellType: cardiomyocyte, CellLineName: MB-231) In contrast, MKK3, MKK4, and MKK6 contribute to p38 MAPK activation caused by UV radiation.  
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11496823:2 
 
-
Sentence  PD98059, a specific inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed the thapsigargin-induced histamine production, the increase in HDC mRNA level and 74-kDa HDC protein expression. 
 
-
CellType  macrophage 
 
-
CellLineName  RAW264.7 
 
-
Source  Ariadne Pathways 
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  9235901:1031 
 
-
Sentence  In the mammalian Erk1/2 pathway, the proximal kinases Raf-1 and B-Raf phosphorylate and activate the dual function threonine/tyrosine kinases MAP/Erk kinases 1 and 2, which in turn phosphorylate Erk1/2. 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v272 i31 p19125 (1997) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/272/31/19125 
 
-
Organ  heart 
 
-
CellType  myocyte 
 
-
CellLineName  AR 
 
-
Source  Ariadne Pathways 
 
</Comment>
</Comment>
-
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-
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     <BiopaxRef>d6b</BiopaxRef>
-
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     <BiopaxRef>dca</BiopaxRef>
-
     <BiopaxRef>a48</BiopaxRef>
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     <BiopaxRef>ac4</BiopaxRef>
-
     <BiopaxRef>fd9</BiopaxRef>
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     <BiopaxRef>a52</BiopaxRef>
-
     <BiopaxRef>de6</BiopaxRef>
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     <BiopaxRef>e6e</BiopaxRef>
 +
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    <Comment>ProtModification MAPK14 --+&gt; ELK4</Comment>
-
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    <Comment>MedLine Reference  9130707 
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+
Sentence  In contrast, the TCF Sap-1a is efficiently phosphorylated by p38 MAP kinase in vitro and in vivo on the homologous residues Ser381 and Ser387. 
 +
Source  Ariadne Pathways 
 +
</Comment>
 +
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 +
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 +
    <Comment>DirectRegulation Ras --+&gt; MAP3K1,</Comment>
 +
    <Comment>7744823 The interaction between Ras and MEKK was GTP-stimulated as measured by the increased phosphorylation of KMMEK1 using GST-Ras (GTP S) beads incubated with recombinant MEKK .
 +
 
 +
7622446 So far, no direct interaction between Ras and MEKK1 has been observed, and it is not clear how it is activated by Ras.
 +
 
 +
11082445 Direct interaction between Ras and MEKK1 may result in the latter being stimulated (Russell et al., 1995 ).
 +
 
 +
8621725 (CellType: t cell, CellLineName: JURKAT) We recently demonstrated that MEKK activity can be stimulated by Ras and that MEKK1 physically binds to Ras in a GTP-dependent manner( 61 , 62 ) .
 +
</Comment>
 +
    <BiopaxRef>f08</BiopaxRef>
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   <Interaction GraphId="df7e4">
-
     <Comment>ProtModification MAPK14 --+&gt; ELK1</Comment>
+
     <Comment>DirectRegulation 1,4,5-Insp3 --+&gt; ITPR1</Comment>
-
     <Comment>MedLine Reference  10781582:1069 
+
     <Comment>11274965 We compared the effects of oxidizing reagents, in particular thimerosal, and of cyclic ADP-ribose (cADPR) on IP3 binding to the various IP3R isoforms.  
-
Sentence  Protein Phosphorylation Assay in Vitro-- Phosphorylation of p53, Elk-1, ATF-2, or c-Jun by active recombinant ERK1, ERK2, p38 kinase or JNK2 was carried out at 30 ???�C for 60 min in the presence of the kinase buffer with 200 ???� M ATP and p53, Elk-1, ATF-2, or c-Jun as substrate. 
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v275 i27 p20444 (2000)
+
-
Journal Link  http://www.jbc.org/cgi/content/full/275/27/20444 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
8633244 IP3 activates the IP3 receptor (IP3R), an intracellular calcium release channel on the endoplasmic reticulum.  
-
MedLine Reference  12208764:1103 
+
-
Sentence  The transactivation domains of ATF2, Elk-1, and c-Jun are physiologically phosphorylated by p38HOG, ERK, and SAPK, respectively. 
+
-
Journal  Cancer Res 
+
-
Journal Reference  v62 i17 p5076 (2002)
+
-
Journal Link  http://cancerres.aacrjournals.org/cgi/content/full/62/17/5076 
+
-
CellLineName  U2 OS 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
9688849 Thus, besides affecting the binding of IP3 to IP3R ( 49 , 50 ), the effects of Mg2+ on the single-channel properties of the IP3R may therefore contribute to the control of temporal and spatial patterns of Ca2+ release from intracellular stores.  
-
MedLine Reference  11732999:1035 
+
-
Sentence  It is reported that Elk-1 and Atf-2 are phosphorylated by ERK and p38 MAPK, respectively [ 30 , 33 , 34 ]. 
+
-
Journal  Eur. J. Biochem 
+
-
Journal Reference  v268 i23 p6058.html) (2001) 
+
-
Journal Link  http://www.ejbiochem.org/cgi/content/full/268/23/6058.h 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
-
MedLine Reference  9054448:1196 
+
-
Sentence  For example, while JNK appears to preferentially phosphorylate c-Jun, ERK/MAPK preferentially phosphorylates c-Myc, p38 MAPK preferentially phosphorylates ATF-2 and ERK/MAPK and p38 MAPK phosphorylate Elk-1 to similar extents ( 68 ). 
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v272 i11 p7464 (1997) 
+
-
Journal Link  http://www.jbc.org/cgi/content/full/272/11/7464 
+
-
Organ  heart 
+
-
CellType  myocyte 
+
-
Source  Ariadne Pathways 
+
-
--------------------------------------------------------------------------------
+
11017917 (CellType: myocyte) IP3 releases Ca2+ from intracellular stores by opening specific Ca2+ channels (IP3R).
 +
 
 +
12621039 (Organ: cerebellar, CellType: Brain Stem, CellLineName: ng108-15) It has been reported that IP3 binding to the IP3R is not cooperative ( 31 , 33 ), and the same property holds true for the wild-type receptor and all of the mutant receptors except D1-223 expressed in R23-11 cells (Table I ).
</Comment>
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-
     <Comment>ProtModification MAPK14 --+&gt; ELK4</Comment>
+
     <Comment>DirectRegulation Gb/g --+&gt; PLC</Comment>
-
     <Comment>MedLine Reference  9130707 
+
     <Comment>Activation of Gi/o-coupled receptors induces dissociation of Galpha from Getagamma, which activates phospholipase C and a resultant generation of the second messengers D - myo -inositol 1,4,5-trisphosphate and diacylglycerol, leading to activation of protein kinase C (PKC).  
-
Sentence  In contrast, the TCF Sap-1a is efficiently phosphorylated by p38 MAP kinase in vitro and in vivo on the homologous residues Ser381 and Ser387.
+
-
Source  Ariadne Pathways 
+
</Comment>
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 +
    <Comment>DirectRegulation RASGRP1 --+&gt; RAP1A</Comment>
 +
    <Comment>11292831 (Organ: brain, CellLineName: PC12D) We next showed in coimmunoprecipitation experiments that CalDAG-GEFI forms a complex with Rap1 and B-Raf following exposure to carbachol or calcium ionophore and the DAG analogue OAG (Fig. 8 ).
 +
 
 +
9789079 (CellLineName: 293T) Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells.
 +
 
 +
14702343 (CellLineName: JURKAT) Our results have demonstrated that forced expression of CalDAG-GEFI activated endogenous Rap1 and augmented adhesion to ICAM-1 in response to TCR stimulation.
 +
 
 +
10835426 (CellLineName: 293T) As reported previously ( 15 , 16 ), CalDAG-GEFI activated Rap1 and, to a lesser extent, R-Ras, and CalDAG-GEFII activated both Ha-Ras and R-Ras
 +
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-
    <Comment>ProtModification MAPK1 --+&gt; ELK1</Comment>
 
-
    <Comment>--------------------------------------------------------------------------------
 
-
MedLine Reference  11454682:1161 
 
-
Sentence  Activated ERK1/2 phosphorylated Elk-1, which involves in the induction of the growth-related genes, suggesting that stimulative effects of low-dose irradiation were mediated by ERK1/2 activation. 
 
-
Journal  Cancer Res 
 
-
Journal Reference  v61 i14 p5396 (2001) 
 
-
Journal Link  http://cancerres.aacrjournals.org/cgi/content/full/61/14/5396 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  10444401:1223 
 
-
Sentence  Once in the nucleus, ERK can phosphorylate and activate transcription factors such as TCF/ELK-1, resulting in c-Fos production and AP-1 complex formation ( 13 , 15 ). 
 
-
Journal  Cell Phys 
 
-
Journal Reference  v277 i2 pC253 (1999) 
 
-
Journal Link  http://ajpcell.physiology.org/cgi/content/full/277/2/C253 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11090049:1273 
 
-
Sentence  Therefore, it has been proposed that Elk1-dependent gene activation can occur independently of SRE/SRF if it can bind to the promoter efficiently. 50 This proposition is supported by the finding that the phosphorylation of Elk1 by ERK2 increases its ability to bind to DNA without interacting with SRF 54 , 55 and by the fact that Elk1 binding is facilitated in transfection experiments with a reporter gene containing multiple high-affinity Elk1 binding sites 40 , 56 or phosphorylation in its C-terminus. 55 , 57 Even though the 9E3/cCAF promoter does not contain an SRE, Elk1 binds to the Elk1 elements and activates transcription, suggesting that thrombin-induced Elk1 activation does not require cooperation with SRF. 
 
-
Journal  Blood 
 
-
Journal Reference  v96 i12 p3696 (2000) 
 
-
Journal Link  http://www.bloodjournal.org/cgi/content/full/96/12/3696 
 
-
Tissue  smooth muscle 
 
-
Organ  umbilical vein 
 
-
CellType  fibroblast 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11812784:1038 
 
-
Sentence  Activated ERK1/2 phosphorylated Elk-1, which involves in the induction of the growth-related genes, suggesting that stimulative effects of low-dose irradiation were mediated by ERK1/2 activation. 
 
-
Journal  EBM 
 
-
Journal Reference  v277 i15 p12532 (2002) 
 
-
Journal Link  http://www.blackwell-synergy.com/links/doi/10.1046/j.1471-4159.2002.01075.x/full/ 
 
-
Tissue  stroma 
 
-
Organ  renal 
 
-
CellType  b cell 
 
-
CellLineName  JEG3 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  10463587:1029 
 
-
Sentence  MAP kinase (MAPK/ERK) phosphorylates Elk-1, which is part of the ternary complex factor that binds to the serum response element in the fos promotor; JNK phosphorylates c-Jun, Elk-1, and ATF-2; and p38 kinase phosphorylates both ternary-complex-factor /Elk-1 and ATF-2. 
 
-
Journal  Cancer Res 
 
-
Journal Reference  v59 i16 p3935 (1999) 
 
-
Journal Link  http://cancerres.aacrjournals.org/cgi/content/full/59/16/3935 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11520792:1024 
 
-
Sentence  TCFs, such as Elk-1, Sap-1, and Fli-1, are targets of the MAPK pathway. 36 , 37 Our data indicated that phosphorylation of Elk-1 by the MEK-ERK1/2 pathway induces Egr-1 expression in LPS-stimulated monocytes and subsequent TF gene expression. 
 
-
Journal  Blood 
 
-
Journal Reference  v98 i5 p1429 (2001) 
 
-
Journal Link  http://www.bloodjournal.org/cgi/content/full/98/5/1429 
 
-
CellType  monocyte 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  12495932:1207 
 
-
Sentence  In summary, this study has demonstrated, in a rat in vivo model, that both serpentine and amphibole asbestos fibers induced protracted phosphorylation of intrapulmonary ERK proteins and upregulated Elk-1 phosphorylation by ERK. 
 
-
Journal  AJRCMB 
 
-
Journal Reference  v28 i1 p51 (2003) 
 
-
Journal Link  http://ajrcmb.atsjournals.org/cgi/content/full/28/1/51 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
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-
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-
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-
    <Comment>ProtModification MAPK3 --+&gt; MAPKAPK2</Comment>
 
-
    <Comment>MedLine Reference  10625698:1036 
 
-
Sentence  Activated MAPK interacts with a number of downstream targets, including the p90 ribosomal S6 kinase (p90 Rsk ) ( 19 ) and MAPK-activated protein kinase-2 (MAPKAP-K2 ) ( 20 , 21 ), which are activated by ERK1/2 and p38 MAPK , respectively. 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v275 i2 p1457 (2000) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/275/2/1457 
 
-
Organ  ventricle 
 
-
CellType  myocyte 
 
-
Source  Ariadne Pathways 
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  7923353:0 
 
-
Sentence  MAPK-activated protein kinase-2 (MAPKAP kinase-2) is activated in vitro by the p42 and p44 isoforms of MAPK (p42/p44MAPK). 
 
-
Source  Ariadne Pathways 
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  8900202:1138 
 
-
Sentence  MBP is an efficient substrate for ERK1 and ERK2, whereas GST-cJun (1-169) includes the activating phosphorylation sites Ser-63 and Ser-73, which have been shown to be phosphorylated by SAPK/JNK but not by ERK1, ERK2, or p38 HOG1 ( 3 ). 2 Similarly, hsp27 is an efficient substrate for MAPKAPK2, which in turn is predominantly activated by p38 HOG1, although MAPKAPK2 can also be phosphorylated in vitro by ERK1 and ERK2 ( 29 , 30 ). -- Fig. 2. 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v271 i43 p27107 (1996) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/271/43/27107 
 
-
CellLineName  Pam 212 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  7592979:1021 
 
-
Sentence  In this article we use a recombinant glutathione S -transferase (GST)-MAPKAP kinase 2-fusion protein and various mutants to study the mechanism of activation of MAPKAP kinase 2 by p44 (ERK1) and p38/40 (RK) in vitro . 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v270 i45 p27213 (1995) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/270/45/27213 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  10753939:1120 
 
-
Sentence  The ERK1 and ERK2 activator, MEK1 , has also been observed to activate MAPKAPK2 ( 58 ). 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v275 i15 p11284 (2000) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/275/15/11284 
 
-
Source  Ariadne Pathways 
 
-
</Comment>
 
-
    <BiopaxRef>a49</BiopaxRef>
 
-
    <BiopaxRef>b42</BiopaxRef>
 
-
    <BiopaxRef>c40</BiopaxRef>
 
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    <BiopaxRef>a59</BiopaxRef>
 
-
    <BiopaxRef>f80</BiopaxRef>
 
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-
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-
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-
    <Comment>ProtModification MAPK3 --+&gt; ELK4</Comment>
 
-
    <Comment>MedLine Reference  9130707 
 
-
Sentence  Sap-1a is phosphorylated by ERK-1. 
 
-
Source  Ariadne Pathways 
 
-
</Comment>
 
-
    <BiopaxRef>ff5</BiopaxRef>
 
-
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-
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-
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-
    <Comment>Type your comment here</Comment>
 
-
    <Comment>MedLine Reference  12842874:1221 
 
-
Sentence  Several other kinases such as CKII, MAPK, PKC, and CaMK are known to phosphorylate CREB and thereby activate CREB-dependent transcription ( 25 , 26 , 29 , 30 , 49 , 56 - 59 ). 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v278 i40 p38860 (2003) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/278/40/38860 
 
-
CellType  b cell 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  10931853:1209 
 
-
Sentence  However, others have suggested that calcium/calmodulin-dependent kinases, Ras/mitogen-activated protein kinase, and protein kinase C can phosphorylate CREB at Ser 133 ( 47-49 ). 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v275 i43 p33365 (2000) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/275/43/33365 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11416000:1287 
 
-
Sentence  CRE- binding protein (CREB) has been reported to be phosphorylated by MAP kinase-activated protein kinase, possibly through p70S6K, as well as cAMP kinase ( 35 , 36 ). 
 
-
Journal  Endocrinology 
 
-
Journal Reference  v142 i7 p2811 (2001) 
 
-
Journal Link  http://endo.endojournals.org/cgi/content/full/142/7/2811 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  10098484:1177 
 
-
Sentence  However, the MEK inhibitor PD98059 was not able to modulate phosphorylation of CREB at a dose that fully inhibited the phosphorylation of MAP kinase (Fig. 6b ). 
 
-
Journal  Endocrinology 
 
-
Journal Reference  v140 i4 p1525 (1999) 
 
-
Journal Link  http://endo.endojournals.org/cgi/content/full/140/4/1525 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  10951185:1095 
 
-
Sentence  This could occur via RSK2, a protein kinase activated by MAP kinases/ERKs, that phosphorylates CREB on its activator site serine 133 [ 43 ]. 
 
-
Journal  Eur. J. Biochem 
 
-
Journal Reference  v267 i17 p5280.html) (2000) 
 
-
Journal Link  http://www.ejbiochem.org/cgi/content/full/267/17/5280.h 
 
-
CellType  dendritic 
 
-
Source  Ariadne Pathways 
 
-
</Comment>
 
-
    <BiopaxRef>d22</BiopaxRef>
 
-
    <BiopaxRef>e2c</BiopaxRef>
 
-
    <BiopaxRef>a90</BiopaxRef>
 
-
    <BiopaxRef>b24</BiopaxRef>
 
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-
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-
    <Comment>ProtModification RPS6KA5 --+&gt; CREB1</Comment>
 
-
    <Comment>MedLine Reference  12414794:1133 
 
-
Sentence  MSK1 has been shown to phosphorylate CREB and to be activated by EGF , as well as ERK1/2 and p38 MAPKs ( 27 ). 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v277 i52 p50550 (2002) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/277/52/50550 
 
-
CellLineName  HeLa 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  12896977:1312 
 
-
Sentence  It is interesting to note that H89 is also a potent inhibitor of protein kinase A (PKA) and that both MSK1 and PKA can phosphorylate CREB. 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v278 i42 p41034 (2003) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/278/42/41034 
 
-
CellType  lymphocyte 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  9687510:1176 
 
-
Sentence  MSK1 phosphorylates CREB at Ser133. ( A ) Comparison of the substrate specificities of MSK1, MAPKAP-K1a and MAPKAP-K1b towards the indicated peptides and CREB. 
 
-
Journal  EMBO 
 
-
Journal Reference  v17 i15 p4426 (1998) 
 
-
Journal Link  http://embojournal.npgjournals.com/cgi/content/full/17/15/4426 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11907026:1243 
 
-
Sentence  MSK-1 phosphorylates CREB in response to FGF or NGF in PC12 cells. 
 
-
Journal  J. Biol. Chem 
 
-
Journal Reference  v277 i21 p18710 (2002) 
 
-
Journal Link  http://www.jbc.org/cgi/content/full/277/21/18710 
 
-
CellLineName  PC 12 
 
-
Source  Ariadne Pathways 
 
-
 
-
--------------------------------------------------------------------------------
 
-
MedLine Reference  11701463:1152 
 
-
Sentence  Activated MSK1 phosphorylates CREB at Ser133. 
 
-
Journal  ATVB 
 
-
Journal Reference  v21 i11 p1764 (2001) 
 
-
Journal Link  http://atvb.ahajournals.org/cgi/content/full/21/11/1764 
 
-
Source  Ariadne Pathways 
 
-
</Comment>
 
-
    <BiopaxRef>ed7</BiopaxRef>
 
-
    <BiopaxRef>b55</BiopaxRef>
 
-
    <BiopaxRef>aa3</BiopaxRef>
 
-
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-
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 +
    <Comment>ChemicalReaction 1,2-Diacetin; PLC; 1,4,5-Insp3,</Comment>
 +
    <Comment>The PLC that hydrolyzes PC-PLC generates the products phosphocholine and DAG.
 +
</Comment>
 +
    <BiopaxRef>a0b</BiopaxRef>
 +
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 +
    <Comment>ProtModification MAP2K1 --+&gt; MAPK1</Comment>
 +
    <Comment>--------------------------------------------------------------------------------
 +
MedLine Reference  10428835:1222 
 +
Sentence  PD98059 is a specific inhibitor for MKK1 and -2 ( 56 ), upstream kinases that phosphorylate and activate ERK ( 15 , 57 ). 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v274 i32 p22569 (1999) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/274/32/22569 
 +
Tissue  cortex 
 +
CellType  neural 
 +
CellLineName  DIV 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12529254:1190 
 +
Sentence  The present study provides direct evidence that the P2X7-R can mediate ERK1/2 activation through a cellular pathway that is dependent on intracellular and extracellular Ca2+, Pyk2, c-Src, PI 3-K, and MEK1/2. 
 +
Journal  Cell Phys 
 +
Journal Reference  v284 i2 pC571 (2003) 
 +
Journal Link  http://ajpcell.physiology.org/cgi/content/full/284/2/C571 
 +
CellType  macrophage 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10827000:1180 
 +
Sentence  MEK1 activity was assayed in muscle protein by measuring the ability of MEK1 immune complexes to phosphorylate a recombinant kinase-inactive MAPK (p42MAPK). 
 +
Journal  Endocrin. Metabol 
 +
Journal Reference  v278 i6 pE992 (2000) 
 +
Journal Link  http://ajpendo.physiology.org/cgi/content/full/278/6/E992 
 +
Tissue  muscle 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12746434:1159 
 +
Sentence  These activation kinetic data are consistent with the fact that ERK1/2 is specifically activated by MEK1/2. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v278 i31 p29000 (2003) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/278/31/29000 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  9207092:1125 
 +
Sentence  Control experiments demonstrated that ERK2 and p38alpha were activated by their cognate MAP kinase kinases, MKK1 and MKK6 (data not shown). 
 +
Journal  PNAS 
 +
Journal Reference  v94 i14 p7337 (1997) 
 +
Journal Link  http://www.pnas.org/cgi/content/full/94/14/7337 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10636870:1150 
 +
Sentence  MEK1/2 inhibition prevents H 2 O 2 -mediated activation of ERK1/2 to a greater extent than activation of p90RSK. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v275 i3 p1739 (2000) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/275/3/1739 
 +
CellLineName  JURKAT 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11303030:1103 
 +
Sentence  The closely related mammalian kinases, ERK1 and ERK2 (also called p44 and p42), are activated by the MEK1/2 kinases in response to mitogenic signals. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v276 i24 p20805 (2001) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/276/24/20805 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11571230:1117 
 +
Sentence  Assessment of VES-induced differentiation after blockage of ERK1/2 activation by MEK1 using the chemical inhibitor PD 98059. 
 +
Journal  Cell Growth and Diff 
 +
Journal Reference  v12 i9 p471 (2001) 
 +
Journal Link  http://cgd.aacrjournals.org/cgi/content/full/12/9/471 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12226077:1214 
 +
Sentence  Expression of dominant negative MEK1 significantly attenuates the bFGF-induced phosphorylation of ERK1/2 (Fig. 3 C , lane 4 on the bottom panel ). 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v277 i46 p44417 (2002) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/277/46/44417 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12960148:1141 
 +
Sentence  Furthermore, S100A1-mediated activation of ERK 1/2 could be prevented by preincubation with PD98095 (2-10 � M ) ( Fig. 6 B ), a specific inhibitor of MEK1 ( 26 , 27 ). 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v278 i48 p48404 (2003) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/278/48/48404 
 +
Source  Ariadne Pathways 
 +
</Comment>
 +
    <BiopaxRef>db1</BiopaxRef>
 +
    <BiopaxRef>a67</BiopaxRef>
 +
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 +
    <Comment>DirectRegulation Gb/g --+&gt; PI3K</Comment>
 +
    <Comment>11879201 Type IB phosphoinositide 3OH-kinase (PI3K) is activated by G-protein betagamma subunits (Gbetagammas).
 +
 +
10642513 A novel p110gamma PI-3K was reported to be activated by G(i)-coupled receptors via Gbetagamma subunits.
 +
 +
11400324 Recent studies have demonstrated that PI3-Kinase can be activated by G beta gamma, but not by G alpha subunit.
 +
 +
11673483 Gbetagamma coimmunoprecipitated with PLCbeta and phosphatidylinositol 3-kinase.
 +
 +
14575867 (CellType: melanophore) In Xenopus aggregation, we suggest that melatonin stimulation of the Mel1c receptor via G(beta gamma) activates PI3-K that, directly or indirectly via MAPK, activates PDE.
 +
 +
7896797 (CellType: platelet) Recent reports indicate that cytosolic PI 3-Ks can also be activated by the beta gamma subunits of heterotrimeric G-proteins (G beta gamma).
 +
 +
12181454 Moreover, it is generally accepted that Getagamma is involved in PI3K activation (Clapham and Neer, 1997 ; Vanhaesebroeck et al., 1997 ).
 +
 +
12796499 It should be noted that it has been well established that PI3K can be activated by the Getagamma-coupled signaling pathway ( 23 – 25 ).
 +
 +
12529253 (Tissue: egg) Moreover, it is generally accepted that Getagamma is involved in PI3K activation ( 1 , 15 ).
 +
 +
10788495 Identity and purity of recombinant PI3Ks, PLC isozymes, and Getagamma dimers.
 +
 +
</Comment>
 +
    <BiopaxRef>edf</BiopaxRef>
 +
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 +
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 +
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 +
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 +
    <Comment>ProtModification PDPK1 --+&gt; PKC</Comment>
 +
    <Comment>11035106 (Tissue: alveola, CellType: macrophage) We then evaluated whether or not PDK-1 might be involved in PKC activation by examining complex formation.
 +
 +
12169624 Interestingly, however, PDK1 can only interact with full-length PKC when it is not phosphorylated at its hydrophobic motif and phosphorylation of this motif was shown to somehow mask this region, preventing it from interacting with PDK1 ( Gao et al ., 2001 ).
 +
 +
11500364 Furthermore, the data appear to exclude a role for members of the PKC family that are also regulated by PDK1 in the regulation of 4E-BP1 phosphorylation: an earlier report indicated a role in this for PKCdelta ( Kumar et al ., 2000 ).
 +
 +
10330161 (CellLineName: PC 12) Very recently, PKCdelta ( 27 ) and PKCeta ( 5 , 27 ) have been shown to be activated by a wortmannin-sensitive, PI-3-kinase-dependent pathway via phosphorylation of PKC by PDK1.
 +
 +
11376011 To probe whether the interaction of protein kinase C with PDK-1 was direct or mediated by a scaffold protein, we examined the interaction of pure PDK-1 with pure protein kinase C.
 +
 +
11971024 Complicating the picture, the PIP 3 -dependent PDK1, besides playing a critical role in activating PKB, has also been shown to phosphorylate/activate various PKC isoforms ( 27 , 28 , 29 ).
 +
 +
10438924 Recent work has shown that PDK1 phosphorylates and activates the p70 S6K kinase ( 86 ), the Sgk protein kinase ( 87 ), and the isoform of protein kinase C (PKC) ( 88 ).
 +
 +
10744767 In this communication, we addressed whether the phosphorylation of protein kinase C by PDK-1 is conformationally regulated.
 +
 +
10861044 PDK-1 has been shown to phosphorylate/activate various PKC isoforms ( 24 , 25 , 26 , 27 , 28 ).
 +
 +
</Comment>
 +
    <BiopaxRef>f98</BiopaxRef>
 +
    <BiopaxRef>da9</BiopaxRef>
 +
    <BiopaxRef>a70</BiopaxRef>
 +
    <BiopaxRef>f57</BiopaxRef>
 +
    <BiopaxRef>bfc</BiopaxRef>
 +
    <BiopaxRef>a47</BiopaxRef>
 +
    <BiopaxRef>cb6</BiopaxRef>
 +
    <BiopaxRef>a51</BiopaxRef>
 +
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    </Graphics>
 +
    <Xref Database="" ID="" />
 +
  </Interaction>
 +
  <Interaction GraphId="ef1a7">
 +
    <Comment>ProtModification MAPK14 --+&gt; ELK1</Comment>
 +
    <Comment>MedLine Reference  10781582:1069 
 +
Sentence  Protein Phosphorylation Assay in Vitro-- Phosphorylation of p53, Elk-1, ATF-2, or c-Jun by active recombinant ERK1, ERK2, p38 kinase or JNK2 was carried out at 30 ???�C for 60 min in the presence of the kinase buffer with 200 ???� M ATP and p53, Elk-1, ATF-2, or c-Jun as substrate. 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v275 i27 p20444 (2000) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/275/27/20444 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12208764:1103 
 +
Sentence  The transactivation domains of ATF2, Elk-1, and c-Jun are physiologically phosphorylated by p38HOG, ERK, and SAPK, respectively. 
 +
Journal  Cancer Res 
 +
Journal Reference  v62 i17 p5076 (2002) 
 +
Journal Link  http://cancerres.aacrjournals.org/cgi/content/full/62/17/5076 
 +
CellLineName  U2 OS 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11732999:1035 
 +
Sentence  It is reported that Elk-1 and Atf-2 are phosphorylated by ERK and p38 MAPK, respectively [ 30 , 33 , 34 ]. 
 +
Journal  Eur. J. Biochem 
 +
Journal Reference  v268 i23 p6058.html) (2001) 
 +
Journal Link  http://www.ejbiochem.org/cgi/content/full/268/23/6058.h 
 +
Source  Ariadne Pathways 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  9054448:1196 
 +
Sentence  For example, while JNK appears to preferentially phosphorylate c-Jun, ERK/MAPK preferentially phosphorylates c-Myc, p38 MAPK preferentially phosphorylates ATF-2 and ERK/MAPK and p38 MAPK phosphorylate Elk-1 to similar extents ( 68 ). 
 +
Journal  J. Biol. Chem 
 +
Journal Reference  v272 i11 p7464 (1997) 
 +
Journal Link  http://www.jbc.org/cgi/content/full/272/11/7464 
 +
Organ  heart 
 +
CellType  myocyte 
 +
Source  Ariadne Pathways 
 +
 +
--------------------------------------------------------------------------------
 +
</Comment>
 +
    <BiopaxRef>fa2</BiopaxRef>
 +
    <BiopaxRef>c4f</BiopaxRef>
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 +
  </Interaction>
 +
  <Interaction GraphId="efe61">
 +
    <Comment>Regulation 1,2-Diacetin --+&gt; RASGRP1,</Comment>
 +
    <Comment>11880369 Diacylglycerol has been shown to regulate RasGRP subcellular location and catalytic activity ( 8 , 15-17 ).
 +
 +
15879121 Y775 and Y783 are therefore identified as the primary regulatory tyrosines for both the IP 3 -mediated Ca 2+ flux and the DAG-mediated activation of the PKC/RasGRP pathway.
 +
 +
17492052 (CellType: platelet) We have recently identified Ca 2+ and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI; also referred to as RasGRP2) as crucial for ��Ω��ΩΩ��Ω��ΩΩΩ 3 integrin activation in platelets ( 15 ).
 +
 +
11395491 (CellType: t cell) IP 3 binds receptors that regulate the release of stored Ca 2+ , whereas DAG is required to activate proteins such as protein kinase C and Ras guanyl nucleotide releasing protein (RasGRP) ( 17-19 ).
 +
 +
15795236 (CellType: t cell) An increase in inositol ( 1 , 4 , 5 ) tris phosphate levels results in release of calcium from intracellular stores, whereas increased diacylglycerol results in stimulation of PKC and RasGRP (for review see reference 30 ).
 +
 +
11292831 (CellLineName: PC12D) Together, these data define a novel signaling pathway for M 1 mAChR , where increases in Ca 2+ and diacylglycerol stimulate the sequential activation of CalDAG-GEFI , Rap1, and B-Raf, resulting in the activation of MEK and ERK1/2.
 +
 +
14532295 (CellType: b cell, CellLineName: ramos) Conversely, diacylglycerol both activates RasGRP1 and causes the activation and translocation of diacylglycerol kinase, which abrogates the activation of the GRP protein ( 43 , 44 ).
 +
 +
14557275 (CellLineName: MOCK) In this regard, it has been reported that DAG kinase zeta phosphorylates specifically localized DAG molecules, thereby controlling the activation of the DAG-activated signaling protein RasGRP and H-Ras ( 20 ).
 +
 +
11257115 (CellLineName: Rat2) It is important then that cells regulate the DAG that activates RasGRP.
 +
 +
11352924 (Organ: brain) DAG produced in response to these external stimuli activates PKC and the guanine nucleotide exchange factors vav and RasGRP ( 39 , 40 ).
 +
 +
</Comment>
 +
    <BiopaxRef>a3f</BiopaxRef>
 +
    <BiopaxRef>ccf</BiopaxRef>
 +
    <BiopaxRef>e1e</BiopaxRef>
 +
    <BiopaxRef>eab</BiopaxRef>
 +
    <BiopaxRef>f1e</BiopaxRef>
 +
    <BiopaxRef>bbe</BiopaxRef>
 +
    <BiopaxRef>c36</BiopaxRef>
 +
    <BiopaxRef>ec3</BiopaxRef>
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    <BiopaxRef>ecb</BiopaxRef>
 +
    <BiopaxRef>bb3</BiopaxRef>
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 +
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 +
    <Comment>MolTransport GNAI2 --+&gt; Gb/g,</Comment>
 +
    <Comment>Alpha-thrombin-mediated phosphatidylinositol 3-kinase activation through release of Gbetagamma dimers from Galphaq and Galphai2.
 +
</Comment>
 +
    <BiopaxRef>cbd</BiopaxRef>
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+
   <Interaction GraphId="f446e">
 +
    <Comment>G protein beta/gamma</Comment>
 +
    <Comment>Binding Gb/g ---- GNAI1</Comment>
 +
    <Comment>12488455 However, the extent of Getagamma binding to GST-Galphai 3-GDP was always greater than to GST (Fig. 3 , A and B ).
 +
 
 +
(Tissue: neuroendocrine, CellLineName: AtT20)
 +
 
 +
</Comment>
 +
    <Comment>15488193 (Tissue: neuroendocrine, CellLineName: AtT20) The particular sequences chosen have been demonstrated to bind selectively to the GDP-bound form of Galphai, but not Galphao, and preclude association of Gbetagamma and Galphai subunits.
 +
</Comment>
 +
    <BiopaxRef>ec8</BiopaxRef>
 +
    <BiopaxRef>fcc</BiopaxRef>
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 +
  <Interaction GraphId="f5603">
 +
    <Comment>Binding GNAI3 ---- HTR1E</Comment>
 +
    <Comment>All the 5-HT(1) receptor types actually interact with G alpha i/G alpha o proteins to inhibit adenylyl cyclase and modulate ionic effectors, i.e. potassium and/or calcium channels.
 +
</Comment>
 +
    <BiopaxRef>f3f</BiopaxRef>
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 +
  </Interaction>
 +
  <Interaction GraphId="f6183">
 +
    <Comment>ProtModification MAPK1 --+&gt; ELK1</Comment>
 +
    <Comment>--------------------------------------------------------------------------------
 +
MedLine Reference  11454682:1161 
 +
Sentence  Activated ERK1/2 phosphorylated Elk-1, which involves in the induction of the growth-related genes, suggesting that stimulative effects of low-dose irradiation were mediated by ERK1/2 activation. 
 +
Journal  Cancer Res 
 +
Journal Reference  v61 i14 p5396 (2001) 
 +
Journal Link  http://cancerres.aacrjournals.org/cgi/content/full/61/14/5396 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10444401:1223 
 +
Sentence  Once in the nucleus, ERK can phosphorylate and activate transcription factors such as TCF/ELK-1, resulting in c-Fos production and AP-1 complex formation ( 13 , 15 ). 
 +
Journal  Cell Phys 
 +
Journal Reference  v277 i2 pC253 (1999) 
 +
Journal Link  http://ajpcell.physiology.org/cgi/content/full/277/2/C253 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11090049:1273 
 +
Sentence  Therefore, it has been proposed that Elk1-dependent gene activation can occur independently of SRE/SRF if it can bind to the promoter efficiently. 50 This proposition is supported by the finding that the phosphorylation of Elk1 by ERK2 increases its ability to bind to DNA without interacting with SRF 54 , 55 and by the fact that Elk1 binding is facilitated in transfection experiments with a reporter gene containing multiple high-affinity Elk1 binding sites 40 , 56 or phosphorylation in its C-terminus. 55 , 57 Even though the 9E3/cCAF promoter does not contain an SRE, Elk1 binds to the Elk1 elements and activates transcription, suggesting that thrombin-induced Elk1 activation does not require cooperation with SRF. 
 +
Journal  Blood 
 +
Journal Reference  v96 i12 p3696 (2000) 
 +
Journal Link  http://www.bloodjournal.org/cgi/content/full/96/12/3696 
 +
Tissue  smooth muscle 
 +
Organ  umbilical vein 
 +
CellType  fibroblast 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11812784:1038 
 +
Sentence  Activated ERK1/2 phosphorylated Elk-1, which involves in the induction of the growth-related genes, suggesting that stimulative effects of low-dose irradiation were mediated by ERK1/2 activation. 
 +
Journal  EBM 
 +
Journal Reference  v277 i15 p12532 (2002) 
 +
Journal Link  http://www.blackwell-synergy.com/links/doi/10.1046/j.1471-4159.2002.01075.x/full/ 
 +
Tissue  stroma 
 +
Organ  renal 
 +
CellType  b cell 
 +
CellLineName  JEG3 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  10463587:1029 
 +
Sentence  MAP kinase (MAPK/ERK) phosphorylates Elk-1, which is part of the ternary complex factor that binds to the serum response element in the fos promotor; JNK phosphorylates c-Jun, Elk-1, and ATF-2; and p38 kinase phosphorylates both ternary-complex-factor /Elk-1 and ATF-2. 
 +
Journal  Cancer Res 
 +
Journal Reference  v59 i16 p3935 (1999) 
 +
Journal Link  http://cancerres.aacrjournals.org/cgi/content/full/59/16/3935 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  11520792:1024 
 +
Sentence  TCFs, such as Elk-1, Sap-1, and Fli-1, are targets of the MAPK pathway. 36 , 37 Our data indicated that phosphorylation of Elk-1 by the MEK-ERK1/2 pathway induces Egr-1 expression in LPS-stimulated monocytes and subsequent TF gene expression. 
 +
Journal  Blood 
 +
Journal Reference  v98 i5 p1429 (2001) 
 +
Journal Link  http://www.bloodjournal.org/cgi/content/full/98/5/1429 
 +
CellType  monocyte 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
MedLine Reference  12495932:1207 
 +
Sentence  In summary, this study has demonstrated, in a rat in vivo model, that both serpentine and amphibole asbestos fibers induced protracted phosphorylation of intrapulmonary ERK proteins and upregulated Elk-1 phosphorylation by ERK. 
 +
Journal  AJRCMB 
 +
Journal Reference  v28 i1 p51 (2003) 
 +
Journal Link  http://ajrcmb.atsjournals.org/cgi/content/full/28/1/51 
 +
Source  Ariadne Pathways 
 +
 
 +
--------------------------------------------------------------------------------
 +
</Comment>
 +
    <BiopaxRef>c2b</BiopaxRef>
 +
    <BiopaxRef>eee</BiopaxRef>
 +
    <BiopaxRef>cad</BiopaxRef>
 +
    <BiopaxRef>e9e</BiopaxRef>
 +
    <BiopaxRef>ea8</BiopaxRef>
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 +
    <Comment>Binding HTR1B ---- serotonin</Comment>
 +
    <Comment>Serotonin treatment of these cells has been reported to inhibit forskolin-stimulated cAMP accumulation in the 5-HT 1B -expressing cells, but not the parental HeLa cells (Hamblin et al., 1992 ). </Comment>
 +
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 +
    <Comment>PromoterBinding SRF --+&gt; FOS</Comment>
 +
    <Comment>--------------------------------------------------------------------------------
 +
Source  Ariadne Pathways 
 +
MedLine Reference  7854423:1 
 +
Sentence  Here we show that the general transcription factor TFIIF is also a target for a transcriptional activator, namely serum response factor (SRF), which binds to the c-fos promoter. 
 +
 
 +
--------------------------------------------------------------------------------
 +
Source  Ariadne Pathways 
 +
MedLine Reference  12788062:0 
 +
Sentence  Serum stimulation leads to activation of the serum response factor (SRF)-mediated transcription of immediate-early genes such as c-fos via various signal transduction pathways. 
 +
 
 +
--------------------------------------------------------------------------------
 +
Source  Ariadne Pathways 
 +
MedLine Reference  9813041:1 
 +
Sentence  The transcription factors Elk-1 and Serum Response Factor are necessary for GH-stimulated transcription of c-fos through the Serum Response Element (SRE). 
 +
 
 +
--------------------------------------------------------------------------------
 +
Source  Ariadne Pathways 
 +
MedLine Reference  9467416:2 
 +
Sentence  The binding of SRF to SRE plays an integral role in c-fos transcription and may occur independently of the association of the ternary complex factors. 
 +
 
 +
--------------------------------------------------------------------------------
 +
Source  Ariadne Pathways 
 +
MedLine Reference  9584171:8 
 +
Sentence  Moreover, TFII-I can form in vivo protein-protein complexes with the c-fos upstream activators SRF, STAT1, and STAT3. 
 +
 
 +
--------------------------------------------------------------------------------
 +
Source  Ariadne Pathways 
 +
MedLine Reference  8864058:3 
 +
Sentence  SRF is hyperphosphorylated in senescent HDFs and fails to bind to the serum-response element in the c-fos promoter.
 +
--------------------------------------------------------------------------------
 +
CellType  fibroblast 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  8413226:4 
 +
Sentence  Phosphorylation of serine 103 significantly enhances the affinity and rate with which SRF associates with its binding site, the serum response element, within the c-fos promoter. 
 +
 
 +
--------------------------------------------------------------------------------
 +
CellLineName  PML-/ 
 +
CellType  promyelocyte 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  12622724:3 
 +
Sentence  PML modulates SRF-mediated c-fos promoter activities upon addition of serum to cells or expression of constitutively active Rho family GTPases. 
 +
 
 +
--------------------------------------------------------------------------------
 +
Tissue  muscle 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  10642500:0 
 +
Sentence  Serum response factor (SRF) is a key transcriptional activator of the c-fos gene and of muscle-specific gene expression. 
 +
 
 +
--------------------------------------------------------------------------------
 +
CellLineName  LEC 
 +
Source  Ariadne Pathways 
 +
MedLine Reference  9570363:5 
 +
Sentence  SRF may play an important role in the development of hepatocellular carcinoma in LEC rats by mediating the proto-oncogene c-fos induction.
 +
</Comment>
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 +
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 +
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 +
    <Comment>DirectRegulation RASGRF1 --+&gt; RHOA</Comment>
 +
    <Comment>11058585 (CellType: neural) We recently isolated a putative GEF , termed p190RhoGEF that binds to RhoA and, when overexpressed in neuronal cells, induces cell rounding and inhibits neurite outgrowth.
 +
 
 +
12496377 (CellType: b cell, CellLineName: WEHI 231) CD40-induced cellular changes and the colocalization of p190RhoGEF with RhoA The enhanced p190RhoGEF expression after a 48-h CD40 stimulation was also shown by an indirect immunofluorescence for endogenous p190RhoGEF in WEHI 231 B cells (Fig. 2 A , 50–60% induction).
 +
</Comment>
 +
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 +
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 +
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 +
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 +
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 +
    <Comment>DirectRegulation RASGRF1 --+&gt; Ras</Comment>
 +
    <Comment>8626650 Here we report that mutations within the switch 2 domain of Ras (residues 62-69) inhibit activation of Ras by the mammalian GEFs, Sos1, and GRF/CDC25Mm.
 +
 
 +
1447167 As a consequence, the CDC25Mm induces a rapid formation of the biologically active Ras.GTP complex.
 +
 
 +
(Tissue: blood, CellType: b cell) Phosphorylation of RasGRP3 by PKC may be critical to modulate its association with Ras at the plasma membrane and the subsequent activation of the ERK MAPK cascade.
 +
 
 +
14749369 Furthermore, we have recently demonstrated that the ability of RasGRF1 to activate Ras is regulated by the Rho family GTPase Cdc42, by a mechanism that entails the translocation of RasGRF1 to the cell particulate fraction ( 3 , 4 ).
 +
 
 +
14676298 (CellType: b cell) This defective Ras activation is suppressed by the expression of RasGRP3 as a membrane-attached form, suggesting that phospholipase C-gamma2 regulates RasGRP3 localization and thereby Ras activation.
 +
 
 +
11500497 Our results suggest that mUBPy may play a role in controlling degradation of CDC25 Mm , thus regulating the level of this Ras-guanine nucleotide exchange factor.
 +
 
 +
15572660 (Tissue: endothelial) However, RasGRP2 is a Rap1 activator and not a Ras activator, whereas RasGRP3 is an activator of Ras and Rap1.
 +
 
 +
15213298 RasGRP3 activates both Ras and Rap1 (Yamashita et al., 2000 ), and RasGRP4 activates Ras (Reuther et al., 2002 ; Yang et al., 2002 ).
 +
 
 +
8717044 (CellLineName: COS-7) These results demonstrate a G-protein-coupled mechanism for Ras activation, mediated by p140 Ras-GRF.
 +
 
 +
8700529 (CellLineName: CHO) Transient expression of CDC25Mm in CHO cells activates Ras.
 +
 
 +
</Comment>
 +
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 +
    <BiopaxRef>c17</BiopaxRef>
 +
    <BiopaxRef>b69</BiopaxRef>
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    <BiopaxRef>a62</BiopaxRef>
 +
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 +
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 +
    <BiopaxRef>c02</BiopaxRef>
 +
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 +
    <BiopaxRef>b63</BiopaxRef>
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-
   <Interaction GraphId="cb469">
+
   <Interaction GraphId="fef9c">
-
     <Comment>Binding ELK4 ---- SRF</Comment>
+
     <Comment>ProtModification MAP3K1 --+&gt; MAP2K2</Comment>
-
    <BiopaxRef>e95</BiopaxRef>
+
     <Comment>9328344 (CellLineName: 293) MEK2 is Activated by MEKK1 and Ligands for Multiple Receptor Types in 293 Cells 293 cells transfected with HA-MEKK1 or empty vector were stimulated with EGF, carbachol, phorbol 12-myristate 13-acetate, and A1F 4 - as described.  
-
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  <Interaction GraphId="bea01">
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-
    <Comment>PromoterBinding ELK1 --+&gt; FOS</Comment>
+
-
     <Comment>--------------------------------------------------------------------------------
+
-
Journal Link  http://www.jimmunol.org/cgi/content/full/167/2/827 
+
-
CellType  t cell 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  11441089:1223 
+
-
Sentence  Elk-1 is known to constitutively associate with serum response factor (SRF) homodimers at the serum response element (SRE) of the 5&amp;apos; c- fos gene DNA promoter/enhancer (reviewed by Cahill et al. in Ref. 28 ). 
+
-
Journal  J. Immunol 
+
-
Journal Reference  v167 i2 p827 (2001) 
+
-
--------------------------------------------------------------------------------
+
12242299 Conceivably, the two compounds may act through distinct mechanisms, in which U-0126 directly suppresses MKK1/2 activity, whereas PD-98059 suppresses MKK1/2 phosphorylation and activation by upstream kinases such as Raf-1 or MEK kinase-1 ( 5 , 17 ).  
-
Journal Link  http://www.jbc.org/cgi/content/full/271/44/27366 
+
-
CellType  t cell 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  8910314:1030 
+
-
Sentence  In addition, JNKs up-regulate c-Fos expression by phosphorylation of the ternary complex factor, p62 TCF (Elk-1), which binds the c- fos promoter ( 23 , 25 ). 
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v271 i44 p27366 (1996) 
+
-
--------------------------------------------------------------------------------
+
-
Journal Link  http://www.jbc.org/cgi/content/full/275/21/16064 
+
-
CellLineName  ags 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  10747974:1309 
+
-
Sentence  Elk-1 binds the c- fos promoter together with the serum response factor ( SRF ) at the serum response element. 
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v275 i21 p16064 (2000) 
+
-
--------------------------------------------------------------------------------
+
-
Journal Link  http://www.jbc.org/cgi/content/full/277/43/40911 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  12145292:1036 
+
-
Sentence  Subsequently, phosphorylated/activated Elk-1 binds the c- fos promoter and allows transcriptional activation of c- fos , an immediate early response gene ( 10 , 11 ).
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v277 i43 p40911 (2002) 
+
-
--------------------------------------------------------------------------------
+
8969228 (CellType: neutrophil) Our data suggest that in human neutrophils both MEK1 and MEK2 are activated by MEKK and that PI 3-kinase may modulate MEKK activation and that of its two downstream components (MEK and MAPK).  
-
Journal Link  http://www.jbc.org/cgi/content/full/273/27/16905 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  9642252:1220 
+
-
Sentence  Elk-1 binds to a serum response element within the c- fos promoter region together with a serum response factor, inducing c-Fos expression ( 42 , 52 , 53 )
+
-
Journal  J. Biol. Chem 
+
-
Journal Reference  v273 i27 p16905 (1998)
+
-
</Comment>
+
-
    <BiopaxRef>e94</BiopaxRef>
+
-
    <BiopaxRef>f81</BiopaxRef>
+
-
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+
-
  <Interaction GraphId="f6964">
+
-
    <Comment>PromoterBinding SRF --+&gt; FOS</Comment>
+
-
    <Comment>--------------------------------------------------------------------------------
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  7854423:1 
+
-
Sentence  Here we show that the general transcription factor TFIIF is also a target for a transcriptional activator, namely serum response factor (SRF), which binds to the c-fos promoter.
+
-
--------------------------------------------------------------------------------
+
11588191 (CellLineName: PC 12) In parallel experiments, we verified that c-MEKK1 led to phosphorylation of MAP kinase through a mechanism involving MEK-1/2 activation by examining effects of the MEK-1/2 inhibitor U0126.  
-
Source  Ariadne Pathways 
+
-
MedLine Reference  12788062:0 
+
-
Sentence  Serum stimulation leads to activation of the serum response factor (SRF)-mediated transcription of immediate-early genes such as c-fos via various signal transduction pathways.
+
-
--------------------------------------------------------------------------------
+
7797459 MEKK1 can activate MKK4, MKK3, MEK1, and MEK2( 27 , 46 , 47 ) , suggesting that MEKKs have a broader substrate specificity than MEKs.  
-
Source  Ariadne Pathways 
+
-
MedLine Reference  9813041:1 
+
-
Sentence  The transcription factors Elk-1 and Serum Response Factor are necessary for GH-stimulated transcription of c-fos through the Serum Response Element (SRE).
+
-
--------------------------------------------------------------------------------
+
9162092 Additionally, the catalytic domain of MEKK1 activated MEK1 and MEK2 in vitro and interacted with MEK in the yeast two-hybrid system.  
-
Source  Ariadne Pathways 
+
-
MedLine Reference  9467416:2 
+
-
Sentence  The binding of SRF to SRE plays an integral role in c-fos transcription and may occur independently of the association of the ternary complex factors.
+
-
--------------------------------------------------------------------------------
+
8940180 Furthermore, expression of MEKK1 in mammalian cells led to the constitutive activation of Mek1 and Mek2 but not of Erk2 ( 34 ).  
-
Source  Ariadne Pathways 
+
-
MedLine Reference  9584171:8 
+
-
Sentence  Moreover, TFII-I can form in vivo protein-protein complexes with the c-fos upstream activators SRF, STAT1, and STAT3.
+
-
--------------------------------------------------------------------------------
+
10918063 (Tissue: squamous, CellType: keratinocyte, CellLineName: TBE) MEKK1 phosphorylates MKK1/2, which then activates two downstream kinases, ERK1 and ERK2, to stimulate the binding of transcription factors to regulate target gene expression ( 68 ).  
-
Source  Ariadne Pathways 
+
-
MedLine Reference  8864058:
+
-
Sentence  SRF is hyperphosphorylated in senescent HDFs and fails to bind to the serum-response element in the c-fos promoter.
+
-
--------------------------------------------------------------------------------
+
-
CellType fibroblast 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  8413226:
+
-
Sentence  Phosphorylation of serine 103 significantly enhances the affinity and rate with which SRF associates with its binding site, the serum response element, within the c-fos promoter.
+
-
--------------------------------------------------------------------------------
 
-
CellLineName  PML-/ 
 
-
CellType  promyelocyte 
 
-
Source  Ariadne Pathways 
 
-
MedLine Reference  12622724:3 
 
-
Sentence  PML modulates SRF-mediated c-fos promoter activities upon addition of serum to cells or expression of constitutively active Rho family GTPases. 
 
-
 
-
--------------------------------------------------------------------------------
 
-
Tissue  muscle 
 
-
Source  Ariadne Pathways 
 
-
MedLine Reference  10642500:0 
 
-
Sentence  Serum response factor (SRF) is a key transcriptional activator of the c-fos gene and of muscle-specific gene expression. 
 
-
 
-
--------------------------------------------------------------------------------
 
-
CellLineName  LEC 
 
-
Source  Ariadne Pathways 
 
-
MedLine Reference  9570363:5 
 
-
Sentence  SRF may play an important role in the development of hepatocellular carcinoma in LEC rats by mediating the proto-oncogene c-fos induction.
 
</Comment>
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-
    <Comment>PromoterBinding CREB1 --+&gt; FOS</Comment>
+
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-
Sentence  In addition to the TCF-SRF complex, the cyclic AMP response element binding protein (CREB), which binds to three separate sequences within the c- fos promoter distinct from the SRE, appears to be required for NGF induction of c- fos transcription ( 5 , 24 ). 
+
-
 
+
-
--------------------------------------------------------------------------------
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  9473689:5 
+
-
Sentence  We propose a model in which inflammation-induced phosphorylation of CREB relieves CREB repression at the DYNCRE3 site, P-CREB binds to the c-Fos promoter, and Fos/Fra, P-CREB, and P-c-Jun interact at the DYNCRE3 site to activate prodynorphin gene transcription. 
+
-
 
+
-
--------------------------------------------------------------------------------
+
-
Journal Link  http://www.jimmunol.org/cgi/content/full/173/5/3557 
+
-
Source  Ariadne Pathways 
+
-
MedLine Reference  15322221:10104 
+
-
Sentence  The site that CREB binds to the c -fos promoter is a CRE centered on the ?57 nt. 
+
-
Journal  J. Immunol 
+
-
Journal Reference  v173 i5 p3557 
+
-
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