GPVI-mediated activation cascade (Homo sapiens)

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4, 7312129133, 225, 10, 2824149, 20272618218, 12, 16, 30246, 15, 23263, 2225191, 2, 173, 2211cytosolVAV3 ATPp-Y173-VAV3 p-Y348-SYK/LCKFYN PIK3R6 LATPIK3R2 PTPN11 RHOA LCK PI(3,4,5)P3FCER1G VAV3 VAV1 RHOA VAV1 Rho/Raceffectors:GTPCollagen type I fibril RAC1 ADPPI(3,4,5)P3 LYN Collagen type I fibril PI3K alpha, beta,gammaG6B:PTPN6,PTPN11PI(3,4,5)P3 VAV1 RHOG PDPK1:PIP3:PKC zetaPDPN FYN p-Y65,Y76-FCER1G PIK3R1 PI3K betaPTPN6 PIK3R6 GPVI:phosphorylatedFcEpsilonR1gamma:FYN:LYN:Collagen type I:p-Y348-SYKCDC42 Collagen type I fibril GDP LYN PIK3CB SYK VAV3 RHOG PDPK1:PIP3:p-T410-PKC zetap-Y348-SYK VAV family:PIP2GPVI:FceRIgamma:FYN:LYN:Collagen type IDAGp-Y348-SYK:p-VAVfamilyPIK3R2 GP6 PTPN6,PTPN11ATPPDPK1p-Y348-SYK:VAVfamilyp-SLP-76:VAVPDPK1 VAV3 ATPCLEC1B dimerPIK3CA VAV1 Rho/Raceffectors:GDPATPVAV1 G6BADPVAV1 VAV1 p-Y172-VAV2 CDC42 LYN p-Y7-CLEC1B SYK PDPK1:PIP3PDPK1 FYN VAV1 RHOG I(1,4,5)P3RHOG ATPGDP p-Y174-VAV1G6B p-Y7-CLEC1B PTPN11 GDPVAV2 Rho/Raceffectors:GTPPIP3:VAV1,2,3RAC1 p-Y7-CLEC1Bdimer:PDPN:SYKp-Y65,Y76-FCER1G RHOA PDPN VAV1,2,3PIK3R1 PIK3R5 SYKRAC1 RAC2 VAV2 PIK3R3 RHOB PIK3CB PTPN6 PRKCZ VAV2 ADPPIK3CG ADPRHOA ADPCDC42 LCP2RHOG PI(4,5)P2 RAC1 FYN p-Y174-VAV1 Collagen type I fibril PI(4,5)P2PLCG2VAV2 p-T410-PRKCZ PIK3CG PDPNPI(3,4,5)P3 VAV3 PIP3 activates AKTsignalingADPp-Y172-VAV2VAV3 Rho/Raceffectors:GDPPI(3,4,5)P3 p-Y200,Y220-LATLYN VAV2 GPVI:phosphorylatedFcEpsilonR1gamma:FYN:LYN:Collagen type ICLEC1B dimer:PDPNp-Y113,128,145-LCP2 GPVI:phosphorylatedFcEpsilonR1gamma:FYN:LYN:Collagen type I:SYKVAV3 Rho/Raceffectors:GTPGTP p-Y348-SYK CDC42 RAC2 p-Y348-SYK PRKCZPI3K gammaPI(4,5)P2CLEC1B p-Y173-VAV3p-PLCG2GTPPDPN p-Y348-SYK VAV2 VAV2 ATPRHOB GP6 p-Y65,Y76-FCER1G RHOG VAV2 Rho/Raceffectors:GDPRAC1 GP6 GTP PIK3R5 GTP PDPK1 ADPp-Y113,128,145-LCP2RHOA GP6 VAV3 p-Y348-SYKCLEC1B ATPRHOA p-Y7-CLEC1Bdimer:PDPNRAC1 VAV familyATPADPPIK3R3 GDP


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.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 114604
Reactome-version 
Reactome version: 66

Quality Tags

Ontology Terms

 

Bibliography

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  1. 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
  2. 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
  3. 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
  4. Watson SP, Auger JM, McCarty OJ, Pearce AC.; ''GPVI and integrin alphaIIb beta3 signaling in platelets.''; PubMed Europe PMC
  5. 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
  6. Sada K, Takano T, Yanagi S, Yamamura H.; ''Structure and function of Syk protein-tyrosine kinase.''; PubMed Europe PMC
  7. 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
  8. 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
  9. 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
  10. Wu J, Motto DG, Koretzky GA, Weiss A.; ''Vav and SLP-76 interact and functionally cooperate in IL-2 gene activation.''; PubMed Europe PMC
  11. 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
  12. 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
  13. 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
  14. 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
  15. Arias-Palomo E, Recuero-Checa MA, Bustelo XR, Llorca O.; ''Conformational rearrangements upon Syk auto-phosphorylation.''; PubMed Europe PMC
  16. 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
  17. 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
  18. 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
  19. Banno Y, Yada Y, Nozawa Y.; ''Purification and characterization of membrane-bound phospholipase C specific for phosphoinositides from human platelets.''; PubMed Europe PMC
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. Jiang Y, Cheng H.; ''Evidence of LAT as a dual substrate for Lck and Syk in T lymphocytes.''; PubMed Europe PMC
  28. 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
  29. 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
  30. 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
  31. 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

History

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CompareRevisionActionTimeUserComment
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)
ATPMetaboliteCHEBI:15422 (ChEBI)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CLEC1B ProteinQ9P126 (Uniprot-TrEMBL)
CLEC1B dimer:PDPNComplexR-HSA-5684824 (Reactome)
CLEC1B dimerComplexR-HSA-5684807 (Reactome)
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)
G6BProteinO95866 (Uniprot-TrEMBL)
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)
GTP MetaboliteCHEBI:15996 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
I(1,4,5)P3MetaboliteCHEBI:16595 (ChEBI)
LATProteinO43561 (Uniprot-TrEMBL)
LCK ProteinP06239 (Uniprot-TrEMBL)
LCP2ProteinQ13094 (Uniprot-TrEMBL)
LYN ProteinP07948 (Uniprot-TrEMBL)
PDPK1 ProteinO15530 (Uniprot-TrEMBL)
PDPK1:PIP3:PKC zetaComplexR-HSA-437191 (Reactome)
PDPK1:PIP3:p-T410-PKC zetaComplexR-HSA-437184 (Reactome)
PDPK1:PIP3ComplexR-HSA-377179 (Reactome)
PDPK1ProteinO15530 (Uniprot-TrEMBL)
PDPN ProteinQ86YL7 (Uniprot-TrEMBL)
PDPNProteinQ86YL7 (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)
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 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.
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)
PTPN6,PTPN11ComplexR-HSA-389744 (Reactome)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC2 ProteinP15153 (Uniprot-TrEMBL)
RHOA ProteinP61586 (Uniprot-TrEMBL)
RHOB ProteinP62745 (Uniprot-TrEMBL)
RHOG ProteinP84095 (Uniprot-TrEMBL)
SYK ProteinP43405 (Uniprot-TrEMBL)
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-Y113,128,145-LCP2 ProteinQ13094 (Uniprot-TrEMBL)
p-Y113,128,145-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/LCKComplexR-HSA-434838 (Reactome)
p-Y348-SYK:VAV familyComplexR-HSA-437941 (Reactome)
p-Y348-SYK:p-VAV familyComplexR-HSA-437934 (Reactome)
p-Y348-SYKProteinP43405 (Uniprot-TrEMBL)
p-Y65,Y76-FCER1G ProteinP30273 (Uniprot-TrEMBL)
p-Y7-CLEC1B dimer:PDPN:SYKComplexR-HSA-5684799 (Reactome)
p-Y7-CLEC1B dimer:PDPNComplexR-HSA-5684816 (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)
ADPArrowR-HSA-5684806 (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)
ATPR-HSA-5684806 (Reactome)
CLEC1B dimer:PDPNArrowR-HSA-5684836 (Reactome)
CLEC1B dimer:PDPNR-HSA-5684806 (Reactome)
CLEC1B dimerR-HSA-5684836 (Reactome)
DAGArrowR-HSA-114689 (Reactome)
G6B:PTPN6,PTPN11ArrowR-HSA-5684169 (Reactome)
G6B:PTPN6,PTPN11TBarR-HSA-453200 (Reactome)
G6B:PTPN6,PTPN11TBarR-HSA-5684801 (Reactome)
G6BR-HSA-5684169 (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)
LATR-HSA-434836 (Reactome)
LCP2R-HSA-429449 (Reactome)
PDPK1:PIP3:PKC zetaArrowR-HSA-437192 (Reactome)
PDPK1:PIP3:PKC zetaR-HSA-437195 (Reactome)
PDPK1:PIP3:PKC zetamim-catalysisR-HSA-437195 (Reactome)
PDPK1:PIP3:p-T410-PKC zetaArrowR-HSA-437195 (Reactome)
PDPK1:PIP3ArrowR-HSA-2316429 (Reactome)
PDPK1:PIP3R-HSA-437192 (Reactome)
PDPK1R-HSA-2316429 (Reactome)
PDPNR-HSA-5684836 (Reactome)
PI(3,4,5)P3ArrowR-HSA-437162 (Reactome)
PI(3,4,5)P3R-HSA-2316429 (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:VAV1,2,3ArrowR-HSA-434637 (Reactome)
PIP3:VAV1,2,3ArrowR-HSA-442273 (Reactome)
PLCG2R-HSA-429497 (Reactome)
PRKCZR-HSA-437192 (Reactome)
PTPN6,PTPN11R-HSA-5684169 (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-2316429 (Reactome) PIP3 generated by PI3K recruits phosphatidylinositide-dependent protein kinase 1 (PDPK1 i.e. PDK1) to the membrane, through its PH (pleckstrin-homology) domain. PDPK1 binds PIP3 with high affinity, and also shows low affinity for PIP2 (Currie et al. 1999).
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). Phosphorylation of SLP-76 is mediated by Syk, analogous to the role of ZAP-70 in phosphorylating T-cell SLP-76 (Bubeck-Wardenberg et al. 1996, Hussain et al. 1999, Fasbender et al. 2017). SLP-76 was shown to bind to tyrosine-phosphorylated C-terminal tail of SYK (de Castro et al. 2012). 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.
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).
R-HSA-5684169 (Reactome) G6B is a member of the immunoglobulin superfamily. The G6B-B variant is the only variant to contain both a transmembrane region and two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that support binding to the SH2 domain-containing protein tyrosine phosphatases PTPN6 (SHP1) and PTPN11 (SHP2) (de Vet et al. 2001, Senis et al. 2007). ITIMs are defined by the consensus sequence (L/I/V/S)-X-Y-X-X-(L/V) and are commonly present in pairs separated by 15 to 30 amino acid residues. ITIM-containing receptors were originally identified by their ability to inhibit signaling by ITAM receptors (Bijsterbosch & Klaus 1985). Expression of the GPVI-FcR gamma-chain complex orC-type lectin domain family 1 member B (CLEC1B, CLEC2) in DT40 (chicken) B cells leads to the generation of both constitutive and agonist-induced signals that are inhibited by G6B. This effect is dependent on the two ITIMs in the cytosolic tail of G6B, but is reported to be independent of the two SH2 domain-containing tyrosine phosphatases PTPN6 and PTPN11, and the inositol lipid 5�²-phosphatase SHIP1 (Mori et al. 2008). A more recent study (Coxon et al. 2011) found that other SH2 domain-containing proteins including SYK and PLCgamma2 also recognize G6B phosphomotifs, which may explain why G6B remains inhibitory in the absence of both PTPN6 and PTPN11.

The tandem SH2 domains of PTPN11 have a 100-fold higher binding affinity for G6B than that of PTPN6. PTPN6 has an absolute binding requirement for phosphorylation at both ITAM motifs, while PTPN11 can associate with G6B when only one motif is phosphorylated. The presence of dual phosphorylated G6B in washed human platelets reduced the EC(50) for both CRP and collagen-induced aggregation (Coxon et al. 2011). G6B is proposed to inhibit sustained constitutive signaling from GPVI-FcRgamma and CLEC1B (Mori et al. 2008).
R-HSA-5684801 (Reactome) Following the phosphorylation of CLEC1B on its hemi-ITAM motif it can bind the kinase SYK (Suzuki-Inoue et al. 2006, 2007, Spalton et al. 2009, Severin et al. 2011). Beyond SYK, CLEC1B signalling is similar to that of GPVI:FcR1 gamma. Murine platelets deficient in Syk or PLC gamma 2 fail to respond to rhodocytin, suggesting they are crucial for Clec1b signal transduction. Mice deficient in the adaptor proteins Linker for activation of T-cells family member 1 (LAT), LCP2 (SLP-76) or the guanine nucleotide exchange factors Vav1-3 are able to respond to high concentrations of rhodocytin, suggesting that these molecules participate in Clec1b signaling but do not prevent signaling when absent (Suzuki-Inoue et al. 2006, Finney et al. 2011).

Clec1b signaling is reduced in the presence of the ITIM-containing immunoglobulin superfamily transmembrane protein G6B (Mori et al. 2008). G6B is thought to act by reducing Syk tyrosine phosphorylation (Mori et al. 2008) but it is possible that the target of inhibition is elsewhere in the CLEC1B signaling cascade.
R-HSA-5684806 (Reactome) Following stimulation by rhodocytin CLEC1B is phosphorylated on the YxxL or hemi-ITAM motif. The kinase responsible for this is not clear. Phosphorylation is suggested to allow the tandem SH2 domains of SYK to bind phosphorylated CLEC1B hemi-ITAM sites (Suzuki-Inoue et al. 2006). GPVI ITAMs are phosphorylated by the Src family kinases FYN and LYN, which results in SYK binding, but CLEC1B appears to be phosphorylated mainly by SYK. The SYK-specific inhibitor R406 inhibits CLEC1B phosphorylation in response to rhodocytin, suggesting SYK is responsible for hemi-ITAM phosphorylation in human platelets (Spalton et al. 2009). However the Src family-specific kinase inhibitor PP2 also inhibits CLEC1B tyrosine phosphorylation (Suzuki-Inoue et al. 2006), suggesting that CLEC1B is phosphorylated by Syk and Src family kinases in human platelets (Suzuki-Inoue et al. 2006, Suzuki-Inoue 2011). Severin et al. (2011) reported that phosphorylation of CLEC1B by rhodocytin is abolished in Syk-deficient mice, while phosphorylation is not altered in mice deficient in the major platelet Src family kinases Fyn, Lyn, Src, or the tyrosine phosphatase CD148, which regulates the basal activity of Src family kinases. The same group also reported that PP2 does not inhibit phosphorylation of mouse Clec1b by rhodocytin, in contrast to the reported effect in human platelets (Suzuki-Inoue et al. 2006), suggesting that Syk phosphorylates Clec1b independently of the Src family kinases in mice.
R-HSA-5684836 (Reactome) C-type lectin domain family 1 member B (CLEC1B, CLEC2) is a 32-kDa C-type lectin-like receptor that dimerizes to form the platelet receptor for the snake venom toxin rhodocytin and the endogenous lymphatic endothelial marker, podoplanin (PDPN) (Suzuki-Inoue et al. 2006, 2007, Christou et al. 2008, Watson et al. 2009). PDPN is a sialomucin-like glycoprotein with a wide tissue distribution. It is found at a high level in lung type I alveolar cells, kidney podocytes, choroid plexus epithelium, lymphatic endothelial cells and fibroblastic reticular cells within secondary lymphoid organs. PDPN is not found on vascular endothelial cells. It is up-regulated in a variety of tumors and on macrophages following lipopolysaccharide stimulation. Cells expressing PDPN or recombinant forms of its extracellular domain have been shown to induce platelet activation (Pollitt et al. 2014).
SYKR-HSA-139842 (Reactome)
SYKR-HSA-5684801 (Reactome)
VAV family:PIP2ArrowR-HSA-434633 (Reactome)
VAV family:PIP2TBarR-HSA-442273 (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-Y113,128,145-LCP2ArrowR-HSA-429449 (Reactome)
p-Y113,128,145-LCP2ArrowR-HSA-429497 (Reactome)
p-Y113,128,145-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/LCKmim-catalysisR-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-Y348-SYKmim-catalysisR-HSA-429449 (Reactome)
p-Y7-CLEC1B dimer:PDPN:SYKArrowR-HSA-114689 (Reactome)
p-Y7-CLEC1B dimer:PDPN:SYKArrowR-HSA-5684801 (Reactome)
p-Y7-CLEC1B dimer:PDPNArrowR-HSA-5684806 (Reactome)
p-Y7-CLEC1B dimer:PDPNR-HSA-5684801 (Reactome)
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