GPVI-mediated activation cascade (Homo sapiens)

From WikiPathways

Revision as of 09:46, 18 November 2015 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
5, 23171, 2012, 22, 24254, 13, 15161, 2072116101, 20193, 8, 142121199, 18cytosolAKT1 PIP3:VAV1,2,3ATPGDP PI(4,5)P2 InterleukinreceptorcomplexeswithactivatedShc:GRB2:p-GAB2:p85-containing Class 1 PI3KsVAV1 GTP p-Y113,Y128,Y145-LCP2Collagen type I fibril PIP3:PDK1:AKT:PKCzetaVAV3 GP6 VAV2 Rho/Raceffectors:GTPADPVAV3 LYN PIK3CB PIK3R1 PI(3,4,5)P3CDC42 PIK3R2 LCK p-Y7-CLEC1Bdimer:PDPN:SYKAKT1 IL2RG PIK3R1 Collagen type I fibril GPVI:phosphorylatedFcEpsilonR1gamma:FYN:LYN:Collagen type ISYK PLCG2Collagen type I fibril p-Y113,Y128,Y145-LCP2 Collagen type I fibril p-Y348-SYK p-Y65,Y76-FCER1G G6B AKT1 VAV3 PI(3,4,5)P3 LYN GTP VAV2 VAV2 GPVI:phosphorylatedFcEpsilonR1gamma:FYN:LYN:Collagen type I:SYKPIK3R2 ADPPIK3CG GPVI:FceRIgamma:FYN:LYN:Collagen type IPIK3R1 PIK3R6 VAV1 FYN ADPp-Y174-VAV1RHOA RHOA LYN GTPFYN p-Y173-VAV3I(1,4,5)P3p-Y172-VAV2 VAV1 p-Y-SHC1 p-SLP-76:VAVVAV1 FYN PDPK1PIK3R3 PIK3CA PIK3CB VAV familyATPATPRHOA AKT3 AKT2 LYN PIK3R2 VAV1 PIK3R3 p-Y348-SYK:VAVfamilyRAC1 VAV3 Rho/Raceffectors:GTPRHOB RHOG G6B:PTPN6,PTPN11ATPADPCDC42 VAV3 VAV3 Rho/Raceffectors:GDPVAV2 SYK FCER1G IL2 RHOG RHOB PI3K gammaRAC2 IL2RA PDK1:AKT:PIP3RAC1 High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks AKTAKT3 PI(3,4,5)P3 LATAKT1 RHOG VAV2 GDP PIK3R6 p-Y-JAK1 PIK3CD p-Y200,Y220-LATADPp-Y7-CLEC1B p-Y348-SYK GP6 PTPN11 PIK3CG PIK3R3 ATPVAV2 AKT2 GPVI:phosphorylatedFcEpsilonR1gamma:FYN:LYN:Collagen type I:p-Y348-SYKGTP PIK3R5 AKT3 PDPK1 p-T410-PRKCZ AKT2 RAC2 PRKCZVAV1 AKT3 PI(3,4,5)P3 PI3K alpha, beta,gammaVAV1 Rho/Raceffectors:GDPPI(4,5)P2FYN CDC42 SYK p-Y364,Y418,Y536-IL2RB p-Y65,Y76-FCER1G PDPK1 VAV3 GP6 p-Y348-SYK:p-VAVfamilyp-Y65,Y76-FCER1G RAC1 SYK/LCKGDP PI(4,5)P2GRB2-1 ADPRHOA VAV1 Rho/Raceffectors:GTPp-Y172-VAV2CDC42 RHOG PI3K betaDAGGDPp-Y-GAB2 PIK3R5 SYKRAC1 PDPN RHOG VAV2 Rho/Raceffectors:GDPPTPN6 p-Y173-VAV3 RAC1 p-Y348-SYKVAV3 ATPAKT2 RAC1 VAV1,2,3PDPK1 RHOG RHOA RHOA PIP3:PDK1:AKT:p(T410)-PKC zetaLCP2ATPp-Y348-SYK PRKCZ JAK3 PIK3CB PI(3,4,5)P3 GP6 VAV2 ADPp-PLCG2PIK3CA VAV family:PIP2p-Y174-VAV1


Description

The GPVI receptor is a complex of the GPVI protein with Fc epsilon R1 gamma (FcR). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FcR complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FcR gamma chain, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation.

The GPVI receptor signaling cascade is similar to that of T- and B-cell immune receptors, involving the formation of a signalosome composed of adapter and effector proteins. At the core of the T-cell receptor signalosome is the transmembrane adapter LAT and two cytosolic adapters SLP-76 and Gads. While LAT is essential for signalling to PLCgamma1 downstream of the T-cell receptor, the absence of LAT in platelets only impairs the activation of PLCgamma2, the response to collagen and GPVI receptor ligands remains sufficient to elicit a full aggregation response. In contrast, GPVI signalling is almost entirely abolished in the absence of SLP-76. View original pathway at:Reactome.

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Chrencik JE, Brooun A, Zhang H, Mathews II, Hura GL, Foster SA, Perry JJ, Streiff M, Ramage P, Widmer H, Bokoch GM, Tainer JA, Weckbecker G, Kuhn P.; ''Structural basis of guanine nucleotide exchange mediated by the T-cell essential Vav1.''; PubMed Europe PMC Scholia
  2. Mangin P, Yuan Y, Goncalves I, Eckly A, Freund M, Cazenave JP, Gachet C, Jackson SP, Lanza F.; ''Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA.''; PubMed Europe PMC Scholia
  3. Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A.; ''Functional and physical interactions of Syk family kinases with the Vav proto-oncogene product.''; PubMed Europe PMC Scholia
  4. Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR.; ''Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.''; PubMed Europe PMC Scholia
  5. Wu J, Motto DG, Koretzky GA, Weiss A.; ''Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation.''; PubMed Europe PMC Scholia
  6. Sada K, Takano T, Yanagi S, Yamamura H.; ''Structure and function of Syk protein-tyrosine kinase.''; PubMed Europe PMC Scholia
  7. Taniguchi T, Kobayashi T, Kondo J, Takahashi K, Nakamura H, Suzuki J, Nagai K, Yamada T, Nakamura S, Yamamura H.; ''Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis.''; PubMed Europe PMC Scholia
  8. Charvet C, Canonigo AJ, Billadeau DD, Altman A.; ''Membrane localization and function of Vav3 in T cells depend on its association with the adapter SLP-76.''; PubMed Europe PMC Scholia
  9. Mori J, Pearce AC, Spalton JC, Grygielska B, Eble JA, Tomlinson MG, Senis YA, Watson SP.; ''G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2.''; PubMed Europe PMC Scholia
  10. de Castro RO, Zhang J, Groves JR, Barbu EA, Siraganian RP.; ''Once phosphorylated, tyrosines in carboxyl terminus of protein-tyrosine kinase Syk interact with signaling proteins, including TULA-2, a negative regulator of mast cell degranulation.''; PubMed Europe PMC Scholia
  11. Hu P, Mondino A, Skolnik EY, Schlessinger J.; ''Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85.''; PubMed Europe PMC Scholia
  12. Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J.; ''Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1.''; PubMed Europe PMC Scholia
  13. Jiang Y, Cheng H.; ''Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytes.''; PubMed Europe PMC Scholia
  14. Kim S, Mangin P, Dangelmaier C, Lillian R, Jackson SP, Daniel JL, Kunapuli SP.; ''Role of phosphoinositide 3-kinase beta in glycoprotein VI-mediated Akt activation in platelets.''; PubMed Europe PMC Scholia
  15. Gross BS, Lee JR, Clements JL, Turner M, Tybulewicz VL, Findell PR, Koretzky GA, Watson SP.; ''Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets.''; PubMed Europe PMC Scholia
  16. Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nürnberg B.; ''Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase.''; PubMed Europe PMC Scholia
  17. Peters JD, Furlong MT, Asai DJ, Harrison ML, Geahlen RL.; ''Syk, activated by cross-linking the B-cell antigen receptor, localizes to the cytosol where it interacts with and phosphorylates alpha-tubulin on tyrosine.''; PubMed Europe PMC Scholia
  18. Gross BS, Melford SK, Watson SP.; ''Evidence that phospholipase C-gamma2 interacts with SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain after stimulation of the collagen receptor glycoprotein VI in human platelets.''; PubMed Europe PMC Scholia
  19. Suzuki-Inoue K, Fuller GL, García A, Eble JA, Pöhlmann S, Inoue O, Gartner TK, Hughan SC, Pearce AC, Laing GD, Theakston RD, Schweighoffer E, Zitzmann N, Morita T, Tybulewicz VL, Ozaki Y, Watson SP.; ''A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2.''; PubMed Europe PMC Scholia
  20. Tartare-Deckert S, Monthouel MN, Charvet C, Foucault I, Van Obberghen E, Bernard A, Altman A, Deckert M.; ''Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte.''; PubMed Europe PMC Scholia
  21. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D.; ''Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav.''; PubMed Europe PMC Scholia
  22. Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A.; ''Regulation of protein kinase C zeta by PI 3-kinase and PDK-1.''; PubMed Europe PMC Scholia
  23. Arias-Palomo E, Recuero-Checa MA, Bustelo XR, Llorca O.; ''Conformational rearrangements upon Syk auto-phosphorylation.''; PubMed Europe PMC Scholia
  24. Goncalves I, Hughan SC, Schoenwaelder SM, Yap CL, Yuan Y, Jackson SP.; ''Integrin alpha IIb beta 3-dependent calcium signals regulate platelet-fibrinogen interactions under flow. Involvement of phospholipase C gamma 2.''; PubMed Europe PMC Scholia
  25. Hussain A, Faryal R, Nore BF, Mohamed AJ, Smith CI.; ''Phosphatidylinositol-3-kinase-dependent phosphorylation of SLP-76 by the lymphoma-associated ITK-SYK fusion-protein.''; PubMed Europe PMC Scholia
  26. Watson SP, Auger JM, McCarty OJ, Pearce AC.; ''GPVI and integrin alphaIIb beta3 signaling in platelets.''; PubMed Europe PMC Scholia
  27. Fasbender F, Claus M, Wingert S, Sandusky M, Watzl C.; ''Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes.''; PubMed Europe PMC Scholia
  28. Suzuki-Inoue K, Tulasne D, Shen Y, Bori-Sanz T, Inoue O, Jung SM, Moroi M, Andrews RK, Berndt MC, Watson SP.; ''Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling.''; PubMed Europe PMC Scholia
  29. Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y.; ''Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells.''; PubMed Europe PMC Scholia
  30. Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMed Europe PMC Scholia
  31. Asselin J, Gibbins JM, Achison M, Lee YH, Morton LF, Farndale RW, Barnes MJ, Watson SP.; ''A collagen-like peptide stimulates tyrosine phosphorylation of syk and phospholipase C gamma2 in platelets independent of the integrin alpha2beta1.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
114659view16:12, 25 January 2021ReactomeTeamReactome version 75
113107view11:17, 2 November 2020ReactomeTeamReactome version 74
112341view15:26, 9 October 2020ReactomeTeamReactome version 73
101241view11:13, 1 November 2018ReactomeTeamreactome version 66
100780view20:40, 31 October 2018ReactomeTeamreactome version 65
100323view19:17, 31 October 2018ReactomeTeamreactome version 64
99868view16:00, 31 October 2018ReactomeTeamreactome version 63
99425view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93862view13:41, 16 August 2017ReactomeTeamreactome version 61
93427view11:23, 9 August 2017ReactomeTeamreactome version 61
87460view14:08, 22 July 2016MkutmonOntology Term : 'hemostasis pathway' added !
87459view14:08, 22 July 2016MkutmonOntology Term : 'signaling pathway' added !
86515view09:19, 11 July 2016ReactomeTeamreactome version 56
83048view09:46, 18 November 2015ReactomeTeamVersion54
81348view12:52, 21 August 2015ReactomeTeamVersion53
76817view08:04, 17 July 2014ReactomeTeamFixed remaining interactions
76521view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
75854view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75554view10:34, 10 June 2014ReactomeTeamReactome 48 Update
74909view13:43, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74553view08:35, 30 April 2014ReactomeTeamReactome46
42049view21:53, 4 March 2011MaintBotAutomatic update
39852view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
AKT1 ProteinP31749 (Uniprot-TrEMBL)
AKT2 ProteinP31751 (Uniprot-TrEMBL)
AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
AKTComplexR-HSA-202088 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
ATPMetaboliteCHEBI:15422 (ChEBI)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
Collagen type I fibril R-HSA-1474201 (Reactome)
DAGMetaboliteCHEBI:17815 (ChEBI)
FCER1G ProteinP30273 (Uniprot-TrEMBL)
FYN ProteinP06241 (Uniprot-TrEMBL)
G6B ProteinO95866 (Uniprot-TrEMBL)
G6B:PTPN6,PTPN11ComplexR-HSA-5684187 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
GP6 ProteinQ9HCN6 (Uniprot-TrEMBL)
GPVI:FceRI gamma:FYN:LYN:Collagen type IComplexR-HSA-434812 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:SYK		ComplexR-HSA-434911 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:p-Y348-SYK		ComplexR-HSA-453171 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I		ComplexR-HSA-434822 (Reactome)
GRB2-1 ProteinP62993-1 (Uniprot-TrEMBL)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
High affinity binding complex dimers of cytokine receptors using Bc, inactive JAK2, p(Y593,628)- Bc:p(427,349,350)-SHC1:GRB2:p(Y)-GAB2:p85-containing Class 1A PI3Ks R-HSA-926776 (Reactome)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
IL2 ProteinP60568 (Uniprot-TrEMBL)
IL2RA ProteinP01589 (Uniprot-TrEMBL)
IL2RG ProteinP31785 (Uniprot-TrEMBL)
Interleukin

receptor complexes with activated

Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks		ComplexR-HSA-912535 (Reactome)
JAK3 ProteinP52333 (Uniprot-TrEMBL)
LATProteinO43561 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCP2ProteinQ13094 (Uniprot-TrEMBL)
LYN ProteinP07948 (Uniprot-TrEMBL)
PDK1:AKT:PIP3ComplexR-HSA-198360 (Reactome)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PDPN ProteinQ86YL7 (Uniprot-TrEMBL)
PI(3,4,5)P3 MetaboliteCHEBI:16618 (ChEBI)
PI(3,4,5)P3MetaboliteCHEBI:16618 (ChEBI)
PI(4,5)P2 MetaboliteCHEBI:18348 (ChEBI)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI3K alpha, beta, gammaComplexR-HSA-437157 (Reactome)
PI3K betaComplexR-HSA-437110 (Reactome)
PI3K gammaComplexR-HSA-392291 (Reactome)
PIK3CA ProteinP42336 (Uniprot-TrEMBL)
PIK3CB ProteinP42338 (Uniprot-TrEMBL)
PIK3CD ProteinO00329 (Uniprot-TrEMBL)
PIK3CG ProteinP48736 (Uniprot-TrEMBL)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R2 ProteinO00459 (Uniprot-TrEMBL)
PIK3R3 ProteinQ92569 (Uniprot-TrEMBL)
PIK3R5 ProteinQ8WYR1 (Uniprot-TrEMBL)
PIK3R6 ProteinQ5UE93 (Uniprot-TrEMBL)
PIP3:PDK1:AKT:PKC zetaComplexR-HSA-437191 (Reactome)
PIP3:PDK1:AKT:p(T410)-PKC zetaComplexR-HSA-437184 (Reactome)
PIP3:VAV1,2,3ComplexR-HSA-5340329 (Reactome)
PLCG2ProteinP16885 (Uniprot-TrEMBL)
PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
PRKCZProteinQ05513 (Uniprot-TrEMBL)
PTPN11 ProteinQ06124 (Uniprot-TrEMBL)
PTPN6 ProteinP29350 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOG ProteinP84095 (Uniprot-TrEMBL)
SYK ProteinP43405 (Uniprot-TrEMBL)
SYK/LCKComplexR-HSA-434838 (Reactome)
SYKProteinP43405 (Uniprot-TrEMBL)
VAV family:PIP2ComplexR-HSA-434632 (Reactome)
VAV familyComplexR-HSA-442295 (Reactome)
VAV1 ProteinP15498 (Uniprot-TrEMBL)
VAV1 Rho/Rac effectors:GDPComplexR-HSA-114543 (Reactome)
VAV1 Rho/Rac effectors:GTPComplexR-HSA-114539 (Reactome)
VAV1,2,3ComplexR-HSA-430172 (Reactome)
VAV2 ProteinP52735 (Uniprot-TrEMBL)
VAV2 Rho/Rac effectors:GDPComplexR-HSA-442278 (Reactome)
VAV2 Rho/Rac effectors:GTPComplexR-HSA-442290 (Reactome)
VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
VAV3 Rho/Rac effectors:GDPComplexR-HSA-442313 (Reactome)
VAV3 Rho/Rac effectors:GTPComplexR-HSA-442315 (Reactome)
p-PLCG2ProteinP16885 (Uniprot-TrEMBL)
p-SLP-76:VAVComplexR-HSA-430155 (Reactome)
p-T410-PRKCZ ProteinQ05513 (Uniprot-TrEMBL)
p-Y-GAB2 ProteinQ9UQC2 (Uniprot-TrEMBL)
p-Y-JAK1 ProteinP23458 (Uniprot-TrEMBL)
p-Y-SHC1 ProteinP29353 (Uniprot-TrEMBL)
p-Y113,Y128,Y145-LCP2 ProteinQ13094 (Uniprot-TrEMBL)
p-Y113,Y128,Y145-LCP2ProteinQ13094 (Uniprot-TrEMBL)
p-Y172-VAV2 ProteinP52735 (Uniprot-TrEMBL)
p-Y172-VAV2ProteinP52735 (Uniprot-TrEMBL)
p-Y173-VAV3 ProteinQ9UKW4 (Uniprot-TrEMBL)
p-Y173-VAV3ProteinQ9UKW4 (Uniprot-TrEMBL)
p-Y174-VAV1 ProteinP15498 (Uniprot-TrEMBL)
p-Y174-VAV1ProteinP15498 (Uniprot-TrEMBL)
p-Y200,Y220-LATProteinO43561 (Uniprot-TrEMBL)
p-Y348-SYK ProteinP43405 (Uniprot-TrEMBL)
p-Y348-SYK:VAV familyComplexR-HSA-437941 (Reactome)
p-Y348-SYK:p-VAV familyComplexR-HSA-437934 (Reactome)
p-Y348-SYKProteinP43405 (Uniprot-TrEMBL)
p-Y364,Y418,Y536-IL2RB ProteinP14784 (Uniprot-TrEMBL)
p-Y65,Y76-FCER1G ProteinP30273 (Uniprot-TrEMBL)
p-Y7-CLEC1B dimer:PDPN:SYKComplexR-HSA-5684799 (Reactome)
p-Y7-CLEC1B ProteinQ9P126 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-114600 (Reactome)
ADPArrowR-HSA-429449 (Reactome)
ADPArrowR-HSA-434836 (Reactome)
ADPArrowR-HSA-437162 (Reactome)
ADPArrowR-HSA-437195 (Reactome)
ADPArrowR-HSA-437936 (Reactome)
ADPArrowR-HSA-453200 (Reactome)
AKTR-HSA-198284 (Reactome)
ATPR-HSA-114600 (Reactome)
ATPR-HSA-429449 (Reactome)
ATPR-HSA-434836 (Reactome)
ATPR-HSA-437162 (Reactome)
ATPR-HSA-437195 (Reactome)
ATPR-HSA-437936 (Reactome)
ATPR-HSA-453200 (Reactome)
DAGArrowR-HSA-114689 (Reactome)
G6B:PTPN6,PTPN11TBarR-HSA-453200 (Reactome)
GDPArrowR-HSA-442273 (Reactome)
GDPArrowR-HSA-442291 (Reactome)
GDPArrowR-HSA-442314 (Reactome)
GPVI:FceRI gamma:FYN:LYN:Collagen type IR-HSA-114600 (Reactome)
GPVI:FceRI gamma:FYN:LYN:Collagen type Imim-catalysisR-HSA-114600 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:SYK		ArrowR-HSA-139842 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:SYK		R-HSA-437118 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:SYK		R-HSA-453200 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:SYK		mim-catalysisR-HSA-453200 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:p-Y348-SYK		ArrowR-HSA-453200 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I:p-Y348-SYK		R-HSA-453183 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I		ArrowR-HSA-114600 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I		ArrowR-HSA-453183 (Reactome)
GPVI:phosphorylated

Fc Epsilon R1

gamma:FYN:LYN:Collagen type I		R-HSA-139842 (Reactome)
GTPR-HSA-442273 (Reactome)
GTPR-HSA-442291 (Reactome)
GTPR-HSA-442314 (Reactome)
I(1,4,5)P3ArrowR-HSA-114689 (Reactome)
Interleukin

receptor complexes with activated

Shc:GRB2:p-GAB2:p85-containing Class 1 PI3Ks		ArrowR-HSA-198284 (Reactome)
LATR-HSA-434836 (Reactome)
LCP2R-HSA-429449 (Reactome)
PDK1:AKT:PIP3ArrowR-HSA-198284 (Reactome)
PDK1:AKT:PIP3R-HSA-437192 (Reactome)
PDPK1R-HSA-198284 (Reactome)
PI(3,4,5)P3ArrowR-HSA-437162 (Reactome)
PI(3,4,5)P3R-HSA-198284 (Reactome)
PI(3,4,5)P3R-HSA-434637 (Reactome)
PI(4,5)P2R-HSA-114689 (Reactome)
PI(4,5)P2R-HSA-434633 (Reactome)
PI(4,5)P2R-HSA-437162 (Reactome)
PI3K alpha, beta, gammamim-catalysisR-HSA-437162 (Reactome)
PI3K betaArrowR-HSA-437118 (Reactome)
PI3K gammaArrowR-HSA-437118 (Reactome)
PIP3:PDK1:AKT:PKC zetaArrowR-HSA-437192 (Reactome)
PIP3:PDK1:AKT:PKC zetaR-HSA-437195 (Reactome)
PIP3:PDK1:AKT:PKC zetamim-catalysisR-HSA-437195 (Reactome)
PIP3:PDK1:AKT:p(T410)-PKC zetaArrowR-HSA-437195 (Reactome)
PIP3:VAV1,2,3ArrowR-HSA-434637 (Reactome)
PLCG2R-HSA-429497 (Reactome)
PRKCZR-HSA-437192 (Reactome)
R-HSA-114600 (Reactome) At the beginning of this reaction, 1 molecule of 'GP VI:Fc Epsilon R1 gamma:Collagen IV complex', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'ADP', and 1 molecule of 'GP VI:phosphorylated Fc Epsilon R1 gamma:Collagen IV complex' are present.

This reaction is mediated by the 'protein-tyrosine kinase activity' of 'GP VI: Fc Epsilon R1 gamma: Collagen IV: SRC'.

R-HSA-114689 (Reactome) At the beginning of this reaction, 1 molecule of '1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate' is present. At the end of this reaction, 1 molecule of '1D-myo-Inositol 1,4,5-trisphosphate', and 1 molecule of '1,2-Diacylglycerol' are present.

This reaction is mediated by the 'phospholipase C activity' of 'Phosphorylated phospholipase C gamma 2'.

R-HSA-139842 (Reactome) Syk binds to the phosphorylated ITAM motif of Fc epsilon R1 gamma chain, each SH2 domain binding a phosphorylated tyrosine. Unlike Zap70, Syk appears to autophosphorylate, so does not require Src family kinases for activation.
R-HSA-198284 (Reactome) Phosphatidylinositides generated by PI3K recruit phosphatidylinositide-dependent protein kinase 1 (PDK1) and AKT (also known as protein kinase B) to the membrane, through their PH (pleckstrin-homology) domains. The binding of PIP3 to the PH domain of AKT is the rate-limiting step in AKT activation. In mammals there are three AKT isoforms (AKT1-3) encoded by three separate genes. The three isoforms share a high degree of amino acid identity and have indistinguishable substrate specificity in vitro. However, isoform-preferred substrates in vivo cannot be ruled out. The relative expression of the three isoforms differs in different mammalian tissues: AKT1 is the predominant isoform in the majority of tissues, AKT2 is the predominant isoform in insulin-responsive tissues, and AKT3 is the predominant isoform in brain and testes. All 3 isoforms are expressed in human and mouse platelets (Yin et al. 2008; O'Brien et al. 2008). Note: all data in the pathway refer to AKT1, which is the most studied.
R-HSA-429449 (Reactome) Stimulation of platelets with collagen-related peptide leads to tyrosine phosphorylation of SLP-76, an adaptor protein with multiple binding domains (Gross et al. 1999). This may be mediated by Syk , analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996). The phosphorylated tyrosine residues provide a binding site for the SH2 domains of downstream signalling proteins like Vav, Itk and ADAP (Jordan et al. 2003). Platelets from mice defective in SLP76 do not connect GPVI engagement with downstream signaling (Clements et al. 1999, Judd et al. 2000). GPVI signaling via SLP-76 does not appear to require LAT or GADS (Judd et al. 2002) suggesting that the mechanism is not identical to that of T-cells. LAT and SLP-76 are both required for P-selectin expression and degranulation but may function independently, or rely on proteins not required by T-cells (Jordan et al. 2003).
R-HSA-429497 (Reactome) SLP-76 has a well-established role in recruitment of PLC gamma 1 in immunoreceptor signalling; its role in the recruitment of PLC gamma 2 in integrin signalling is less clear. Results from SLP-76 null mice imply a functional role in GPVI signalling. Platelets from SLP-76 null mice exhibit a marked reduction in spreading and a decrease in whole cell phosphotyrosine levels when adhered to a fibrinogen-coated surface. In vivo reconstitution of SLP-76 by retroviral gene transfer corrects bleeding diathesis and restores normal responses to both collagen and fibrinogen (Judd et al., 2000).
R-HSA-430158 (Reactome) SLP-76 is a hematopoietic cell-specific adapter protein. Studies indicate that three phosphotyrosines in SLP-76 (Y113, Y128, and Y145) are required for interactions with the SH2 domains of Vav1 (and Nck and Itk). This interaction is essential for membrane recruitment of Vav1. Similarly, association of Vav3 with SLP-76 was found to be essential for membrane recruitment. Vav2 has been shown to interact with SLP-76 in resting Jurkat cells.
R-HSA-434633 (Reactome) Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides.
R-HSA-434637 (Reactome) Vav interacts directly with PIP2 and PIP3, with a fivefold selectivity for PIP3 over PIP2. PIP3 gives a twofold stimulation of Vav1 GEF activity while PIP2 leads to 90% inhibition. Binding probably occurs through the PH domain, known to bind phosphoinositides.
R-HSA-434836 (Reactome) Activated Syk (or possibly the related kinase Lck) phosphorylates two key tyrosine residues of LAT.
R-HSA-437118 (Reactome) GPVI downstream signaling involves PI3K. Mouse knockouts of PI3Kbeta/PI3Kgamma suggest that though both isoforms are required for a full platelet response, only beta is absolutely required for Akt phosphorylation, Rap1 activation, and platelet aggregation downstream. The pathway connecting GPVI to PI3K is unclear. Two possible routes are suggested by interactions of the PI3K p85 regulatory subunit with LAT and with peptides representing the ITAM motif of Fc Epsilon R1 gamma.
R-HSA-437162 (Reactome) Class I Phosphoinositide 3-kinases (PI3Ks) are heterodimeric proteins, each having a catalytic subunit of 110-120 kDa and an associated regulatory subunit. PI3Ks alpha, beta and delta share a common regulatory p85 subunit, PI3K gamma has a p101 regulatory subunit. All the class I PI3Ks are able to phosphorylate PtdIns, PtdIns-4-P, or PtdIns-4,5-P2 (PIP2) on the free 3-position, and have a strong preference for PIP2.They are activated by receptor tyrosine kinases and by Ras and Rho family GTPases.
R-HSA-437192 (Reactome) 3-phosphoinositide dependent protein kinase-1 (PDK1) and Protein kinase C zeta type (PKC zeta) are associated in fibroblasts. PDK1, also known as Protein kinase B kinase (PKBK), is known to co-localise with Protein kinase B (PKB) in transfected fibroblasts and platelets, suggesting a complex of PDK1, PKB and PKC zeta.
R-HSA-437195 (Reactome) 3-phosphoinositide dependent protein kinase-1 (PDK1, also known as PKB kinase because of its activity at Protein kinase B) phosphorylates T410 of Protein kinase C zeta type (PKC zeta), leading to activation. The motif surrounding T410 is highly conserved in other PKC family members suggesting that PDK1 might activate other PKCs.
R-HSA-437932 (Reactome) The SH2 region of Vav1 binds to Syk at a site including phosphorylated tyrosine Y348. Mutation of this residue to F abolishes binding and subsequent Vav1 phosphorylation. Vav2 has also been shown to bind Syk.
R-HSA-437936 (Reactome) Tyrosine phosphorylateion is believed to be a general activation mechansim for the Vav family. VAV1 Tyr-174 binds to the Dbl homology region, inhibiting GEF activity. Phosphorylation of this residue by Syk relieves inhibition, activating Vav1. In Jurkat cells T-cell receptor activation leads to increased Vav2 tyrosine phosphorylation; the expression of Lck, Fyn, Zap70, or Syk stimulated this phosphorylation. Vav is regulated downstream of the thrombin and thrombopoietin receptors (Miyakawa et al. 1997) and integrins, including the major platelet integrin alphaIIbbeta3. Vav family proteins are involved in filopodia and lamellipodia formation; mouse platelets deficient in Vav1 and Vav3 exhibit reduced filopodia and lamellipodia formation during spreading on fibrinogen. This is accompanied by reduced alphaIIbbeta3-mediated PLCgamma2 tyrosine phosphorylation and reduced Ca(2+) mobilization (Pearce et al. 2007).
R-HSA-442273 (Reactome) Vav family members are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav1 is a GEF for Rac1, Rac2 and RhoG, and possibly RhoA and Cdc42
R-HSA-442291 (Reactome) Members of the Vav family are guanine nucleotide exchange factors (GEFs) for Rho-family GTPases. Vav2 is a GEF for RhoA, RhoB and RhoG, and possibly Rac1 and Cdc42
R-HSA-442314 (Reactome) Vav3 is a guanine nucleotide exchange factors (GEF) for RhoA, RhoB and to a lesser extent Rac1.
R-HSA-453183 (Reactome) Structural and biophysical studies indicate that the adaptability of the Syk tandem SH2 domains is made possible by relatively weak interactions between the two SH2 domains and the flexibility of interdomain A (Zhang et al. 2008). A large proportion of phosphorylated Syk is released into the cytosol. One factor that has been proposed for modulating the interactions of Syk with the receptor ITAM is the phosphorylation of Syk on Y130 (Keshvara et al. 1997).
R-HSA-453200 (Reactome) Binding of Syk causes conformational changes that lead to Syk activation by autophosphorylation. Syk can be activated by a number of phosphorylation events, and it has been proposed that Syk may function as a switch whereby any of several possible stimuli trigger the acquisition of similar activated conformations. (Tsang et al. 2008). These phosphorylations both modulate Syk's catalytic activity (Keshvara et al. 1997) and generate docking sites for SH2 domain-containing proteins, such as c-Cbl, PLC, and Vav1. Syk tyrosine phosphorylation is reduced in the presence of the ITIM-containing immunoglobulin superfamily transmembrane protein G6B (Mori et al. 2008).
SYK/LCKmim-catalysisR-HSA-434836 (Reactome)
SYKArrowR-HSA-429449 (Reactome)
SYKR-HSA-139842 (Reactome)
SYKR-HSA-429449 (Reactome)
VAV family:PIP2ArrowR-HSA-434633 (Reactome)
VAV familyR-HSA-434633 (Reactome)
VAV familyR-HSA-437932 (Reactome)
VAV1 Rho/Rac effectors:GDPR-HSA-442273 (Reactome)
VAV1 Rho/Rac effectors:GTPArrowR-HSA-442273 (Reactome)
VAV1,2,3R-HSA-430158 (Reactome)
VAV1,2,3R-HSA-434637 (Reactome)
VAV2 Rho/Rac effectors:GDPR-HSA-442291 (Reactome)
VAV2 Rho/Rac effectors:GTPArrowR-HSA-442291 (Reactome)
VAV3 Rho/Rac effectors:GDPR-HSA-442314 (Reactome)
VAV3 Rho/Rac effectors:GTPArrowR-HSA-442314 (Reactome)
p-PLCG2ArrowR-HSA-429497 (Reactome)
p-PLCG2mim-catalysisR-HSA-114689 (Reactome)
p-SLP-76:VAVArrowR-HSA-430158 (Reactome)
p-Y113,Y128,Y145-LCP2ArrowR-HSA-429449 (Reactome)
p-Y113,Y128,Y145-LCP2ArrowR-HSA-429497 (Reactome)
p-Y113,Y128,Y145-LCP2R-HSA-429497 (Reactome)
p-Y113,Y128,Y145-LCP2R-HSA-430158 (Reactome)
p-Y172-VAV2mim-catalysisR-HSA-442291 (Reactome)
p-Y173-VAV3mim-catalysisR-HSA-442314 (Reactome)
p-Y174-VAV1mim-catalysisR-HSA-442273 (Reactome)
p-Y200,Y220-LATArrowR-HSA-434836 (Reactome)
p-Y348-SYK:VAV familyArrowR-HSA-437932 (Reactome)
p-Y348-SYK:VAV familyR-HSA-437936 (Reactome)
p-Y348-SYK:VAV familymim-catalysisR-HSA-437936 (Reactome)
p-Y348-SYK:p-VAV familyArrowR-HSA-437936 (Reactome)
p-Y348-SYKArrowR-HSA-453183 (Reactome)
p-Y348-SYKR-HSA-437932 (Reactome)
p-Y7-CLEC1B dimer:PDPN:SYKArrowR-HSA-114689 (Reactome)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP1826"
Personal tools