T-Cell Receptor and Co-stimulatory Signaling (Bos taurus)

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2protein-protein interactionProliferationLEGENDLCKZAP70PIP2LAT / SLP-76 scaffold complexPIP3PLCG1ITKAKT1PRKCAPTPN6P13KCa2+Bcl-xLErkNFKB1AP-1 NFATC2RASA1Ras-GTPDAGIP3CalmodulinRASGRP1IL2PPP3CANFKBIAIKK complexinhibitionactivation / recruitmentphosphorylationdephosphorylationnecessary precursorPTENPDK1SurvivalRas-GDPPIP2signaling moleculetranscription factortarget geneMHC peptideB7-1/ B7-2B7-1/ B7-2PD-L1ligandNFATC2PCSNK1A1GSK3AGSK3BDYRK1ADYRK2NRON1FYNTCRATCRBCD8ACD8BCD28CTLA4PDCD1


Description

The activation and translocation of transcription factors NFAT, AP-1 and NF-kappa-B via the co-stimulatory signaling cascade triggered by MHC peptide, B7 proteins and PD-L1. The activation of NFAT involves a Ca2+/calcineurin disruption of a massive RNA-protein complex prior to its translocation into the nucleus and ultimate transcription factor activity.

Comments

HomologyMapper 
This pathway was inferred from Homo sapiens pathway WP2583_96058 with a 72.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

  1. Takahashi K, Yan I, Haga H, Patel T; ''Long non-coding RNA in liver diseases.''; Hepatology, 2014 PubMed
  2. Srikanth S, Gwack Y; ''Orai1-NFAT signalling pathway triggered by T cell receptor stimulation.''; Mol Cells, 2013 PubMed

History

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CompareRevisionActionTimeUserComment
96324view09:16, 8 March 2018Mkutmonremoved redundant ontology tags
96323view09:13, 8 March 2018MkutmonOntology Term : 'calcineurin signaling pathway' added !
96322view09:13, 8 March 2018MkutmonOntology Term : 'Toll-like receptor signaling pathway' added !
96321view09:13, 8 March 2018MkutmonOntology Term : 'nuclear factor of activated T-cells signaling pathway' added !
96320view09:12, 8 March 2018MkutmonUpdated homology conversion
85869view10:16, 19 June 2016EgonwReplaced a mim-conversion with Arrow.
80937view15:32, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProductENSBTAG00000017636 (Ensembl)
  • Akt is a serine/threonine-specific protein kinase that plays a key role in many cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. Akt is recruited to the membrane by PIP3. Here Akt can be activated / phosphorylated (indirectly) by P13K and can then phosphorylate a variety of downstream pathways. Noteably, Akt promotes cell survival by inhibiting the cell death pathway and stimulates cell metabolism by increasing the utilization of glucose.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:207
AP-1 ProteinA heterodimeric protein composed of proteins belonging to the c-Fos, c-Jun, ATF and JDP families
B7-1/ B7-2Complex
Bcl-xLProteinBcl-xL is a transmembrane protein in the mitochondria. It is a anti-apoptosis protein because it prevents release of cytochrome c from the mitochondria.
CD28GeneProductENSBTAG00000007445 (Ensembl)
  • CD28 is a co-stimulatory surface receptor. It bind B7-1 and B7-2. After CD28 binds its ligand, it is phosphorylated by Lck. The effect of this phosphorylation activates P13K to generate PIP3 which recruits Itk to the cell membrane where Lck can phosphorylate it. Then Itk-P can recruit PLC-g
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:940
CD8AGeneProductENSBTAG00000021141 (Ensembl)
  • CD8 co-receptor - alpha subunit
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:925
CD8BGeneProductENSBTAG00000008956 (Ensembl)
  • CD8 co-receptor - beta subunit
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:926
CSNK1A1GeneProductENSBTAG00000005326 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1452
CTLA4GeneProductENSBTAG00000013170 (Ensembl)
  • Expression is enhanced by IL-2.

    Function is controlled largely by regulation of its surface expression. Initially CTLA-4 is in the intracellular membrane but moves to the cell surface after T-cell receptor signaling. When CTLA-4 cytoplasmic tail is NOT phosphorylated it binds to AP-2 (clathrin adapter molecule) and is removed from the surface. When the tail is phosphorylated AP-2 cannot bind and CTLA-4 is expressed on the surface. CTLA-4 competes with CD28 for B7 ligand, and it has a higher affinity of B7 in part because CTLA-4 binds B7 in a dimer.

    CTLA-4 interfers with the formation of lipid rafts, TCR:ZAP70 microclusters, and central supramolecular activation complex.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1493
Ca2+MetaboliteHMDB00464 (HMDB) Calcium ions are second messengers, small-molecule biochemical mediators. Calcium is released from the ER by IP3. It diffuses throughough the cell enabling the signal to activate a variety of taget proteins. A certain calcium ion concentration must be acheived before targets can be activated.
CalmodulinProtein
  • Calmodulin is a calcium binding protein. Binding Ca ions induces a conformational change allowing calmodulin to bind to and regulate a variety of effector proteins.
  • No homologues found for original id L:801
DAGMetaboliteHMDB07223 (HMDB) Produced from PIP2 cleaveage by PLC-g. DAG is a membrane protein which can now recruit other signaling molecules to the membrane by serving as a binding target.
DYRK1AGeneProductENSBTAG00000001771 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:1859
DYRK2GeneProductENSBTAG00000007256 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:8445
ErkProteinErk is MAP kinase that is phosphorylated by MAPKK, Mek. SHP's and PP2A may also dephosphorylate Erk to some extent.
FYNGeneProductENSBTAG00000011851 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:2534
GSK3AGeneProductENSBTAG00000020756 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:2931
GSK3BGeneProductENSBTAG00000048057 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:2932
IKK complexGeneProductIKK is a complex of serine kinases. It phosphorylates IkB, stimulating IkB's ubiquitination which targets IkB for degradation by the proteasome.
IL2GeneProductENSBTAG00000020883 (Ensembl)
  • All three TFs (NFAT, AP-1, and NFkB) a needed to initiate IL-2 transcription.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:3558
IP3MetaboliteHMDB01059 (HMDB) IP3 is generated when PLC-g cleaves PIP2. IP3 is a second messanger that diffuses into the cytosol and binds to IP3 receptors on the ER therey opening calcium channels.
ITKProteinENSBTAG00000000306 (Ensembl)
  • Itk is a membrane associated tryosine kinase. It binds to phosphorylated LAT and SLP-76 scafflods. From here is activates PLC-g by phosphorylation
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:3702
LAT / SLP-76 scaffold complexProteinLinker for Activation of T cells - LAT is a transmembrane scaffold protein. It can be phosphorylated by Zap-70. This scaffold includes LAT, SLP-76, Grb2, SOS, GADS
LCKGeneProductENSBTAG00000012695 (Ensembl)
  • Cytoplasmic tyrosine kinase - Lck in its inactive state is bound to CD4/CD8 cytoplasmic tail and it's terminal tyrosine is phosphorylated. Dephosphorylation of this amino acid (by tyrosine phosphotase CD45 -- CD4/CD8 binding its ligand) causes a conformations change in LcK and it becomes an active tyrosine kinase.

    LcK is activated when the extracellular part of CD8 binds its (MHC:peptide) ligand. Lck is a Src family kinase that is constitutively expressed. It phosphorylates all TCR ITAMS.

    Rephosphorylation of this carboxyl-terminal tyrosine by Csk returns Lck to the inactive state.

    Basically, Lck is bound to CD8. When CD8 binds MHC:peptide, Lck gets activated and can phosphorylate nearby ITAMs.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:3932
MHC peptideComplex
NFATC2ProteinENSBTAG00000018270 (Ensembl)
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4773
NFKB1GeneProductENSBTAG00000020270 (Ensembl)
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:4790
NFKBIAProteinENSBTAG00000016683 (Ensembl)
  • IkB is an inhibitory protein which when bound to NFkB holds it in an inactive state.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = S:P25963
NRONGeneProductENSBTAG00000044315 (Ensembl)
  • NRON is a long non-coding RNA
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = En:ENSG00000253079
P13KProteinP13K converts membrane lipid PIP2 to PIP3 by adding a phosphate. P13K activity is dependent upon CD28 co-stimulation because P13K can bind to phosphorylated ITIMs on CD28. PI3K can also bind ICOS
PD-L1Complex
PDCD1GeneProductENSBTAG00000011543 (Ensembl)
  • PD-1 is repressed by pro-inflammatry cytokines. It's ligand, PD-L1, is constitutively expressed on T-cells. PD-1 contains a ITIM (immunoreceptor tyrosine-based inhibitory motif) in its cytoplasmic tail. When this ITIM is phosphorylated, it recruits either of 2 inhibitory phosphatases called SHP
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5133
PDK1GeneProductENSBTAG00000016836 (Ensembl)
  • Phosphoinositide-dependent kinase-1: recruited to the membrane by docking at PIP3 and phosphorylates/activates Akt
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5163
PIP2MetaboliteHMDB10059 (HMDB) PIP2 is a membrane lipid.
PIP3MetaboliteHMDB10147 (HMDB) PIP3 is a membrane lipid generated from PIP2 by the enzyme P13K. PIP3 has a PH binding domain that can be recognized by PLC-g, Itk, and Atk.
PLCG1GeneProductENSBTAG00000017584 (Ensembl)
  • PLC-g is a phospholipase, a class of enzymes that cleave phospholipids just before the phosphate group.

    PLC-g is initially brought to the plasma membrane by binding of its PH domain to membrane lipid PIP3. PLC-g then binds to LAT and SLP-76 and can be activated by Itk mediated phosphorylation.

    PLC-g ultimately produces 3 different second messangers to activate 3 paths leading to different TFs that lead to IL-2 transcription
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5335
PPP3CAGeneProductENSBTAG00000016005 (Ensembl)
  • Calcineurin is a protein phosphatase that acts on NFAT.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5530
PRKCAGeneProductENSBTAG00000001061 (Ensembl) Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5578
PTENProteinENSBTAG00000009498 (Ensembl)
  • Phosphatase and tensin homolog - PTEN is constitutively expressed and is a PIP3 phosphatase.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5728
PTPN6GeneProductENSBTAG00000020294 (Ensembl)
  • SHP-1/2 are tyrosine phosphatases. Here, SHP removes phosphates from PIP3 reverting it back to PIP2. (reverses the work of tyrosine kinase P13K) SHP is recruited to the PD-1 cytoplasmic tail when PD-1 ITIMs are phosphorylated.
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5777
RASA1GeneProductENSBTAG00000009565 (Ensembl)
  • Ras-GAP rapidly downregulates the activity of Ras by converting its bound GTP to GDP
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:5921
RASGRP1GeneProductENSBTAG00000021872 (Ensembl)
  • RasGRP binds to DAG in the membrane where it can activate Ras
  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:10125
Ras-GDPProteinRas is a small G protein of GTPase. It is located in the membrane, and it acts as a molecular switch. It is inactive when bound to GDP, but becomes active when GDP is switched for GTP. Binding the GTP induces a conformational change in Ras thus enabling it to bind to and do other things.
Ras-GTPProteinRas is a small G protein of GTPase. It is located in the membrane, and it acts as a molecular switch. It is inactive when bound to GDP, but becomes active when GDP is switched for GTP. Binding the GTP induces a conformational change in Ras thus enabling it to bind to and do other things.
TCRAGeneProduct
TCRBGeneProduct
ZAP70GeneProductENSBTAG00000005892 (Ensembl)
  • ZAP-70 is kinase that becomes activated after phosphorylation. It contains to tandem SH2 domains that bind to phosphorylated ITAMs on the TCR complex cytoplasmic tails.

    It docks at the TCR (requires both ITAM positions to be phosphorylated), is then phosphorylated by Lck, and then recruits other signaling proteins.

  • Homology Mapping from Homo sapiens to Bos taurus: Original ID = L:7535

Annotated Interactions

No annotated interactions
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