Signaling by PTK6 (Homo sapiens)

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1, 6, 9, 12, 15...69563, 145, 15622, 10114054, 122, 1319582952340, 117105, 164823527, 10033231141142210027, 10010210512282825451, 67, 11418, 70, 92, 9984, 103, 121709546, 776346, 1451176383, 10411484, 1213561011019510254104114cytosolnucleoplasmHBEGF:EGFR:p-Y525-GPNMBp-Y342-PTK6 UBC(381-456) ADPADPp-Y31,Y118-PXNHRAS Signaling by EGFRPTPN1 ADPRegulation ofHypoxia-inducibleFactor (HIF) byoxygenp-Y342-PTK6:ARHGAP35DOCK1 CDK4 ADPCDKN1B:(CDK4:CCND1,(CDK2:CCNE1))p-Y525-GPNMB ATPATPCCNE1 p-Y435,Y440,Y443-KHDRBS1p-Y342-PTK6:AKT1PTK6 GeneARAP1 p-Y342-PTK6RHOA UBB(1-76) p-Y165,Y664-BCAR1p-Y342-PTK6 p-Y705-STAT3 ARHGAP35 p-Y231-ARAP1HIF1A,EPAS1:PTK6Genep-Y342-PTK6 ADPLRRK2p-Y342-PTK6 KRAS HBEGF(63-148) p-Y342-PTK6 GTP KRAS SOCS3 GeneHBEGF:EGFR:p-Y525-GPNMB:LINC01139:PTK6:LRRK2RHO GTPases activateCITp-Y342-PTK6 Phosphorylated p-Y877-ERBB2 heterodimers PTK6 Gene EPAS1 KHDRBS2p-Y342-PTK6:CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ELMO2 CBLp-Y1105-ARHGAP35RPS27A(1-76) BCAR1NRAS p-Y525-GPNMB SOCS3LINC01139GDPp-Y362-DOK1RASA1 ATPRHO GTPases activateIQGAPsPTK6 Gene p-Y342-PTK6 H2Op-Y342-PTK6:p-Y250-STAP2p-Y342-PTK6 STAP2p-Y1105-ARHGAP35:RHOA:GTPp-Y1105-ARHGAP35:RASA1BCAR1 p-Y342-PTK6:BCAR1PELP1RHO GTPases ActivateWASPs and WAVEsp-Y88-CDKN1B DOK1UBC(1-76) SemaphorininteractionsADPCCND1 HBEGF(63-148) GPNMBGDP UBA52(1-76) p-Y342-PTK6 HBEGF(63-148) RHOA LRRK2 p-Y342-PTK6DOK1 RHO GTPases activateKTN1UBB(153-228) AKT1EGFR p-Y705-STAT3ADPGDP NRAS HBEGF:EGFR:GPNMBHBEGF:EGFR:p-Y525-GPNMB:LINC01139:p-Y351-PTK6:LRRK2p-Y351-PTK6 NR3C1:DexamethasonePXNPTK6Gene:EPAS1:NR3C1:Dexamethasone:PELP1p-Y705-STAT3dimer:SOCS3 GeneATPSOCS3 GTP KHDRSB3p-Y705-STAT3 CCND1 p-Y88-CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))PIP3 activates AKTsignalingKRAS Phosphorylated p-Y877-ERBB2 heterodimers p-Y342-PTK6:PTPN1PiATPADPDEXA UBB(77-152) PolyUb,p-Y700,Y731,Y774-CBLELMO1 PELP1 p-Y565,S797-HIF1ADEXA NR3C1 ADPCDK2 p-Y31,Y118-PXN:CRK:DOCK180:ELMO1,ELMO2RAF/MAP kinasecascadep-Y435,Y440,Y443-KHDRBS1CDK2 CRK LRRK2 ATPCRK EPAS1 PTK6p-Y342-PTK6 RAC1:GTPp-Y342-PTK6:SOCS3ADPp-Y342-PTK6:PXNPhosphorylated p-6Y-ERBB2 heterodimers UBC(609-684) RHOA:GTPHBEGF:EGFRNR3C1 p-Y250-STAP2 ATPPTK6 NRAS EGFR ATPHIF1A,EPAS1p-Y342,Y447-PTK6p-Y342-PTK6:KHDRBS1PiRHO GTPases activatePKNsADPATPLINC01139 p-Y-KHDRBS2p21 RAS:GTPATPHBEGF(63-148) GTP LINC01139 ATPUbUBC(229-304) KHDRBS1 HRAS p-Y342-PTK6 UBC(533-608) RHO GTPases activatePAKsCCNE1 p-Y250-STAP2 RASA1UBC(153-228) p-Y-SFPQp-Y700,Y731,Y774-CBLEGFR SFPQCDKN1B p-Y-KHDRSB3CDKN1B Signaling by ERBB2EPAS1 ADPp-Y342-PTK6:p-Y250-STAP2:STAT3GTP CDK4 RAC1 ADPGTP p-Y342-PTK6 EGFR RAC1 p21 RAS:GTP:RASA1CDK4 p-Y1105-ARHGAP35 EGFR p21 RAS:GDPKHDRBS1S Phasep-Y1105-ARHGAP35 p-ERBB2heterodimers:PTK6p-Y525-GPNMB PTK6 CRK:DOCK180:ELMO1,ELMO2HIF1AAKT1 RHOA p-Y31,Y118-PXN Phosphorylated p-6Y-ERBB2 heterodimers p-Y315,Y326-AKT1 DOCK1 EPAS1ATPELMO1 CCNE1 CDK2 ATPUBC(457-532) CCND1 PTPN1HRAS ARAP1RHO GTPases ActivateForminsATPp-Y705-STAT3 dimerUBC(77-152) p-ERBB2 heterodimersADPUBC(305-380) RASA1 p-Y342-PTK6 p-Y705-STAT3 dimerSTAT3 SRMSADPSOCS3 Gene p-Y342-PTK6:p-Y315,Y326-AKT1STAT3ELMO2 STAP2 p-Y342-PTK6 GDP RHOA:GDPp-Y342-PTK6:ARAP1GPNMB ATPp-Y705-STAT3 Mitotic G1-G1/SphasesHBEGF(63-148) GTPp-Y342-PTK6:STAP2HIF1A p-Y342-PTK6:DOK1HIF1A RAC1:GDPARHGAP35PXN 17, 52, 69, 94, 108...3, 7, 20, 30, 38...821145, 10, 16, 26, 42...667, 114952, 37, 57, 62, 68...951006363, 15613, 24, 32, 55, 59...95105, 16461, 88, 119, 15111, 34, 91, 96, 107...1022228, 4910154278210514, 25, 39, 44, 113...4, 8, 19, 29, 41...351142231, 43, 79, 143, 15384869511777


Description

PTK6 (BRK) is an oncogenic non-receptor tyrosine kinase that functions downstream of ERBB2 (HER2) (Xiang et al. 2008, Peng et al. 2015) and other receptor tyrosine kinases, such as EGFR (Kamalati et al. 1996) and MET (Castro and Lange 2010). Since ERBB2 forms heterodimers with EGFR and since MET can heterodimerize with both ERBB2 and EGFR (Tanizaki et al. 2011), it is not clear if MET and EGFR activate PTK6 directly or act through ERBB2. Levels of PTK6 increase under hypoxic conditions (Regan Anderson et al. 2013, Pires et al. 2014). The kinase activity of PTK6 is negatively regulated by PTPN1 phosphatase (Fan et al. 2013) and SRMS kinase (Fan et al. 2015), as well as the STAT3 target SOCS3 (Gao et al. 2012).

PTK6 activates STAT3-mediated transcription (Ikeda et al. 2009, Ikeda et al. 2010) and may also activate STAT5-mediated transcription (Ikeda et al. 2011). PTK6 promotes cell motility and migration by regulating the activity of RHO GTPases RAC1 (Chen et al. 2004) and RHOA (Shen et al. 2008), and possibly by affecting motility-related kinesins (Lukong and Richard 2008). PTK6 crosstalks with AKT1 (Zhang et al. 2005, Zheng et al. 2010) and RAS signaling cascades (Shen et al. 2008, Ono et al. 2014) and may be involved in MAPK7 (ERK5) activation (Ostrander et al. 2007, Zheng et al. 2012). PTK6 enhances EGFR signaling by inhibiting EGFR down-regulation (Kang et al. 2010, Li et al. 2012, Kang and Lee 2013). PTK6 may also enhance signaling by IGF1R (Fan et al. 2013) and ERBB3 (Kamalati et al. 2000).<p>PTK6 promotes cell cycle progression by phosphorylating and inactivating CDK inhibitor CDKN1B (p27) (Patel et al. 2015).<p>PTK6 activity is upregulated in osteopontin (OPN or SPP1)-mediated signaling, leading to increased VEGF expression via PTK6/NF-kappaB/ATF4 signaling path. PTK6 may therefore play a role in VEGF-dependent tumor angiogenesis (Chakraborty et al. 2008).<p>PTK6 binds and phosphorylates several nuclear RNA-binding proteins, including SAM68 family members (KHDRSB1, KHDRSB2 and KHDRSB3) (Derry et al. 2000, Haegebarth et al. 2004, Lukong et al. 2005) and SFPQ (PSF) (Lukong et al. 2009). The biological role of PTK6 in RNA processing is not known.<p>For a review of PTK6 function, please refer to Goel and Lukong 2015. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8848021
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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  125. Kitzing TM, Wang Y, Pertz O, Copeland JW, Grosse R.; ''Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC.''; PubMed
  126. Daniels RH, Bokoch GM.; ''p21-activated protein kinase: a crucial component of morphological signaling?''; PubMed
  127. Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1.''; PubMed
  128. Bashour AM, Fullerton AT, Hart MJ, Bloom GS.; ''IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments.''; PubMed
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  132. Sadasivam S, DeCaprio JA.; ''The DREAM complex: master coordinator of cell cycle-dependent gene expression.''; PubMed
  133. Cheng M, Sexl V, Sherr CJ, Roussel MF.; ''Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).''; PubMed
  134. Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed
  135. Swart-Mataraza JM, Li Z, Sacks DB.; ''IQGAP1 is a component of Cdc42 signaling to the cytoskeleton.''; PubMed
  136. Maesaki R, Ihara K, Shimizu T, Kuroda S, Kaibuchi K, Hakoshima T.; ''The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1.''; PubMed
  137. Parrini MC, Lei M, Harrison SC, Mayer BJ.; ''Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.''; PubMed
  138. Plotnikov A, Zehorai E, Procaccia S, Seger R.; ''The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation.''; PubMed
  139. Guan KL, Jenkins CW, Li Y, O'Keefe CL, Noh S, Wu X, Zariwala M, Matera AG, Xiong Y.; ''Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4.''; PubMed
  140. Fan G, Aleem S, Yang M, Miller WT, Tonks NK.; ''Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.''; PubMed
  141. Bagchi S, Weinmann R, Raychaudhuri P.; ''The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F.''; PubMed
  142. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA.; ''Mutations of the BRAF gene in human cancer.''; PubMed
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  147. Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D.; ''Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB.''; PubMed
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  155. Kaelin WG, Ratcliffe PJ.; ''Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.''; PubMed
  156. Minoguchi M, Minoguchi S, Aki D, Joo A, Yamamoto T, Yumioka T, Matsuda T, Yoshimura A.; ''STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif.''; PubMed
  157. Lukong KE, Richard S.; ''Breast tumor kinase BRK requires kinesin-2 subunit KAP3A in modulation of cell migration.''; PubMed
  158. Nezami AG, Poy F, Eck MJ.; ''Structure of the autoinhibitory switch in formin mDia1.''; PubMed
  159. Tanizaki J, Okamoto I, Sakai K, Nakagawa K.; ''Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification.''; PubMed
  160. Zong H, Raman N, Mickelson-Young LA, Atkinson SJ, Quilliam LA.; ''Loop 6 of RhoA confers specificity for effector binding, stress fiber formation, and cellular transformation.''; PubMed
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History

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102035view16:22, 26 November 2018Marvin M2Ontology Term : 'PW:0000003' removed !
102034view16:21, 26 November 2018Marvin M2Ontology Term : 'kinase mediated signaling pathway' added !
101698view14:35, 1 November 2018DeSlOntology Term : 'signaling pathway' added !
101490view11:35, 1 November 2018ReactomeTeamreactome version 66
101027view21:15, 31 October 2018ReactomeTeamreactome version 65
100725view20:11, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT1ProteinP31749 (Uniprot-TrEMBL)
ARAP1 ProteinQ96P48 (Uniprot-TrEMBL)
ARAP1ProteinQ96P48 (Uniprot-TrEMBL)
ARHGAP35 ProteinQ9NRY4 (Uniprot-TrEMBL)
ARHGAP35ProteinQ9NRY4 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (ChEBI)
BCAR1 ProteinP56945 (Uniprot-TrEMBL)
BCAR1ProteinP56945 (Uniprot-TrEMBL)
CBLProteinP22681 (Uniprot-TrEMBL)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCNE1 ProteinP24864 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK4 ProteinP11802 (Uniprot-TrEMBL)
CDKN1B ProteinP46527 (Uniprot-TrEMBL)
CDKN1B:(CDK4:CCND1,(CDK2:CCNE1))ComplexR-HSA-8848419 (Reactome)
CRK ProteinP46108 (Uniprot-TrEMBL)
CRK:DOCK180:ELMO1,ELMO2ComplexR-HSA-2029141 (Reactome)
DEXA MetaboliteCHEBI:41879 (ChEBI)
DOCK1 ProteinQ14185 (Uniprot-TrEMBL)
DOK1 ProteinQ99704 (Uniprot-TrEMBL)
DOK1ProteinQ99704 (Uniprot-TrEMBL)
EGFR ProteinP00533 (Uniprot-TrEMBL)
ELMO1 ProteinQ92556 (Uniprot-TrEMBL)
ELMO2 ProteinQ96JJ3 (Uniprot-TrEMBL)
EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
EPAS1ProteinQ99814 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GPNMB ProteinQ14956 (Uniprot-TrEMBL)
GPNMBProteinQ14956 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBEGF(63-148) ProteinQ99075 (Uniprot-TrEMBL)
HBEGF:EGFR:GPNMBComplexR-HSA-8857546 (Reactome)
HBEGF:EGFR:p-Y525-GPNMB:LINC01139:PTK6:LRRK2ComplexR-HSA-8857567 (Reactome)
HBEGF:EGFR:p-Y525-GPNMB:LINC01139:p-Y351-PTK6:LRRK2ComplexR-HSA-8857574 (Reactome)
HBEGF:EGFR:p-Y525-GPNMBComplexR-HSA-8857556 (Reactome)
HBEGF:EGFRComplexR-HSA-8857547 (Reactome)
HIF1A ProteinQ16665 (Uniprot-TrEMBL)
HIF1A,EPAS1:PTK6 GeneComplexR-HSA-8848808 (Reactome)
HIF1A,EPAS1ComplexR-HSA-8848802 (Reactome)
HIF1AProteinQ16665 (Uniprot-TrEMBL)
HRAS ProteinP01112 (Uniprot-TrEMBL)
KHDRBS1 ProteinQ07666 (Uniprot-TrEMBL)
KHDRBS1ProteinQ07666 (Uniprot-TrEMBL)
KHDRBS2ProteinQ5VWX1 (Uniprot-TrEMBL)
KHDRSB3ProteinO75525 (Uniprot-TrEMBL)
KRAS ProteinP01116 (Uniprot-TrEMBL)
LINC01139 ProteinENST00000400946 (Ensembl)
LINC01139RnaENST00000400946 (Ensembl)
LRRK2 ProteinQ5S007 (Uniprot-TrEMBL)
LRRK2ProteinQ5S007 (Uniprot-TrEMBL)
Mitotic G1-G1/S phasesPathwayR-HSA-453279 (Reactome) Mitotic G1-G1/S phase involves G1 phase of the mitotic interphase and G1/S transition, when a cell commits to DNA replication and divison genetic and cellular material to two daughter cells.

During early G1, cells can enter a quiescent G0 state. In quiescent cells, the evolutionarily conserved DREAM complex, consisting of the pocket protein family member p130 (RBL2), bound to E2F4 or E2F5, and the MuvB complex, represses transcription of cell cycle genes (reviewed by Sadasivam and DeCaprio 2013).

During early G1 phase in actively cycling cells, transcription of cell cycle genes is repressed by another pocket protein family member, p107 (RBL1), which forms a complex with E2F4 (Ferreira et al. 1998, Cobrinik 2005). RB1 tumor suppressor, the product of the retinoblastoma susceptibility gene, is the third member of the pocket protein family. RB1 binds to E2F transcription factors E2F1, E2F2 and E2F3 and inhibits their transcriptional activity, resulting in prevention of G1/S transition (Chellappan et al. 1991, Bagchi et al. 1991, Chittenden et al. 1991, Lees et al. 1993, Hiebert 1993, Wu et al. 2001). Once RB1 is phosphorylated on serine residue S795 by Cyclin D:CDK4/6 complexes, it can no longer associate with and inhibit E2F1-3. Thus, CDK4/6-mediated phosphorylation of RB1 leads to transcriptional activation of E2F1-3 target genes needed for the S phase of the cell cycle (Connell-Crowley et al. 1997). CDK2, in complex with cyclin E, contributes to RB1 inactivation and also activates proteins needed for the initiation of DNA replication (Zhang 2007). Expression of D type cyclins is regulated by extracellular mitogens (Cheng et al. 1998, Depoortere et al. 1998). Catalytic activities of CDK4/6 and CDK2 are controlled by CDK inhibitors of the INK4 family (Serrano et al. 1993, Hannon and Beach 1994, Guan et al. 1994, Guan et al. 1996, Parry et al. 1995) and the Cip/Kip family, respectively.

NR3C1 ProteinP04150 (Uniprot-TrEMBL)
NR3C1:DexamethasoneComplexR-HSA-879850 (Reactome)
NRAS ProteinP01111 (Uniprot-TrEMBL)
PELP1 ProteinQ8IZL8 (Uniprot-TrEMBL)
PELP1ProteinQ8IZL8 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PTK6 Gene:EPAS1:NR3C1:Dexamethasone:PELP1ComplexR-HSA-8856931 (Reactome)
PTK6 Gene ProteinENSG00000101213 (Ensembl)
PTK6 GeneGeneProductENSG00000101213 (Ensembl)
PTK6 ProteinQ13882 (Uniprot-TrEMBL)
PTK6ProteinQ13882 (Uniprot-TrEMBL)
PTPN1 ProteinP18031 (Uniprot-TrEMBL)
PTPN1ProteinP18031 (Uniprot-TrEMBL)
PXN ProteinP49023 (Uniprot-TrEMBL)
PXNProteinP49023 (Uniprot-TrEMBL)
Phosphorylated p-6Y-ERBB2 heterodimers R-HSA-1963585 (Reactome)
Phosphorylated p-Y877-ERBB2 heterodimers R-HSA-1963580 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
PolyUb,p-Y700,Y731,Y774-CBLProteinP22681 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1:GDPComplexR-HSA-5674631 (Reactome)
RAC1:GTPComplexR-HSA-442641 (Reactome)
RAF/MAP kinase cascadePathwayR-HSA-5673001 (Reactome) The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RASA1 ProteinP20936 (Uniprot-TrEMBL)
RASA1ProteinP20936 (Uniprot-TrEMBL)
RHO GTPases Activate ForminsPathwayR-HSA-5663220 (Reactome) Formins are a family of proteins with 15 members in mammals, organized into 8 subfamilies. Formins are involved in the regulation of actin cytoskeleton. Many but not all formin family members are activated by RHO GTPases. Formins that serve as effectors of RHO GTPases belong to different formin subfamilies but they all share a structural similarity to Drosophila protein diaphanous and are hence named diaphanous-related formins (DRFs).

DRFs activated by RHO GTPases contain a GTPase binding domain (GBD) at their N-terminus, followed by formin homology domains 3, 1, and 2 (FH3, FH1, FH2) and a diaphanous autoregulatory domain (DAD) at the C-terminus. Most DRFs contain a dimerization domain (DD) and a coiled-coil region (CC) in between FH3 and FH1 domains (reviewed by Kuhn and Geyer 2014). RHO GTPase-activated DRFs are autoinhibited through the interaction between FH3 and DAD which is disrupted upon binding to an active RHO GTPase (Li and Higgs 2003, Lammers et al. 2005, Nezami et al. 2006). Since formins dimerize, it is not clear whether the FH3-DAD interaction is intra- or intermolecular. FH2 domain is responsible for binding to the F-actin and contributes to the formation of head-to-tail formin dimers (Xu et al. 2004). The proline-rich FH1 domain interacts with the actin-binding proteins profilins, thereby facilitating actin recruitment to formins and accelerating actin polymerization (Romero et al. 2004, Kovar et al. 2006).

Different formins are activated by different RHO GTPases in different cell contexts. FMNL1 (formin-like protein 1) is activated by binding to the RAC1:GTP and is involved in the formation of lamellipodia in macrophages (Yayoshi-Yamamoto et al. 2000) and is involved in the regulation of the Golgi complex structure (Colon-Franco et al. 2011). Activation of FMNL1 by CDC42:GTP contributes to the formation of the phagocytic cup (Seth et al. 2006). Activation of FMNL2 (formin-like protein 2) and FMNL3 (formin-like protein 3) by RHOC:GTP is involved in cancer cell motility and invasiveness (Kitzing et al. 2010, Vega et al. 2011). DIAPH1, activated by RHOA:GTP, promotes elongation of actin filaments and activation of SRF-mediated transcription which is inhibited by unpolymerized actin (Miralles et al. 2003). RHOF-mediated activation of DIAPH1 is implicated in formation of stress fibers (Fan et al. 2010). Activation of DIAPH1 and DIAPH3 by RHOB:GTP leads to actin coat formation around endosomes and regulates endosome motility and trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007). Endosome trafficking is also regulated by DIAPH2 transcription isoform 3 (DIAPH2-3) which, upon activation by RHOD:GTP, recruits SRC kinase to endosomes (Tominaga et al. 2000, Gasman et al. 2003). DIAPH2 transcription isoform 2 (DIAPH2-2) is involved in mitosis where, upon being activated by CDC42:GTP, it facilitates the capture of astral micr