Platelet Adhesion to exposed collagen (Homo sapiens)

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2, 42371, 65cytosolGPVI:FceRIgamma:FYN:LYNMg2+ VWF(23-763) GP1BA GP9 GP6 LYNCollagen type IfibrilGPVI:FceRIgamma:FYN:LYN:Collagen type IGP VI : FceRI gammadimerGP1BA ITGA1 LYN Integrinalpha1beta1,alpha2beta1,alpha10beta1ITGA10 ITGA2 FCERIG dimerITGB1 GP1BB GP6 Mg2+FYNGP5 Collagen type I fibril VWF(23-763)Collagen type I fibril ITGA2 Collagen type I fibril FCER1G GP9 ITGA10 GP5 GpIb-IX-V:Collagentype I fibril:vWFITGB1 VWF(23-763) FCER1G FYN Collagen type I fibril GP6FCER1G FCER1G FYN GP1BB GP6 Integrinsalpha1beta1,alpha2beta1:Collagen type I fibril:Mg2+ITGA1 GPIb-IX-VLYN Collagen type Ifibril:vWF


Initiation of platelet adhesion is the first step in the formation of the platelet plug. Circulating platelets are arrested and subsequently activated by exposed collagen and vWF. It is not entirely clear which type of collagen is responsible for adhesion and activation; collagen types I and III are abundant in vascular epithelia but several other types incluing IV are present (Farndale 2006). Several collagen binding proteins are expressed on platelets, including integrin alpha2 beta1, GPVI, and GPIV. Integrin alpha2 beta1, known on leukocytes as VLA-2, is the major platelet collagen receptor (Kunicki et al. 1988). It requires Mg2+ to interact with collagen and may require initiation mediated by the activation of integrin alphaIIb beta3 (van de Walle 2007). Binding occurs via the alpha2 subunit I domain to a collagen motif with the sequence Gly-Phe-Hyp-Gly-Glu-Arg (Emsley 2000). Binding of collagen to alpha2 beta1 generates intracellular signals that contribute to platelet activation. These facilitate the engagement of the lower-affinity collagen receptor, GPVI (Keely 1996), the key receptor involved in collagen-induced platelet activation. The GPVI receptor is a complex of the GPVI protein with a dimer of Fc epsilon R1 gamma (FceRI gamma). The Src family kinases Fyn and Lyn constitutively associate with the GPVI:FceRIgamma complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in FceRI gamma, leading to binding and activation of the tyrosine kinase Syk. Downstream of Syk, a series of adapter molecules and effectors lead to platelet activation. vWF protein is a polymeric structure of variable size. It is secreted in two directions, by the endothelium basolaterally and into the bloodstream. Shear-induced aggregation is achieved when vWF binds via its A1 domain to GPIb (part of GPIb-IX-V), and via its A3 domain mediating collagen binding to the subendothelium. The interaction between vWF and GPIb is regulated by shear force; an increase in the shear stress results in a corresponding increase in the affinity of vWF for GPIb. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 75892
Reactome version: 66
Reactome Author 
Reactome Author: de Bono, Bernard

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  1. Watson SP, Auger JM, McCarty OJ, Pearce AC.; ''GPVI and integrin alphaIIb beta3 signaling in platelets.''; PubMed Europe PMC
  2. Tsuji M, Ezumi Y, Arai M, Takayama H.; ''A novel association of Fc receptor gamma-chain with glycoprotein VI and their co-expression as a collagen receptor in human platelets.''; PubMed Europe PMC
  3. 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
  4. Miura Y, Takahashi T, Jung SM, Moroi M.; ''Analysis of the interaction of platelet collagen receptor glycoprotein VI (GPVI) with collagen. A dimeric form of GPVI, but not the monomeric form, shows affinity to fibrous collagen.''; PubMed Europe PMC
  5. Kroll MH, Harris TS, Moake JL, Handin RI, Schafer AI.; ''von Willebrand factor binding to platelet GpIb initiates signals for platelet activation.''; PubMed Europe PMC
  6. Gibbins JM, Okuma M, Farndale R, Barnes M, Watson SP.; ''Glycoprotein VI is the collagen receptor in platelets which underlies tyrosine phosphorylation of the Fc receptor gamma-chain.''; PubMed Europe PMC
  7. Turitto VT, Weiss HJ, Zimmerman TS, Sussman II.; ''Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion.''; PubMed Europe PMC


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101506view11:37, 1 November 2018ReactomeTeamreactome version 66
101042view21:18, 31 October 2018ReactomeTeamreactome version 65
100573view19:51, 31 October 2018ReactomeTeamreactome version 64
100122view16:36, 31 October 2018ReactomeTeamreactome version 63
99672view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93851view13:40, 16 August 2017ReactomeTeamreactome version 61
93409view11:22, 9 August 2017ReactomeTeamreactome version 61
88096view09:29, 26 July 2016RyanmillerOntology Term : 'homeostasis pathway' added !
88095view09:28, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86499view09:19, 11 July 2016ReactomeTeamreactome version 56
83074view09:53, 18 November 2015ReactomeTeamVersion54
81394view12:55, 21 August 2015ReactomeTeamVersion53
76862view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76567view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75900view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75600view10:45, 10 June 2014ReactomeTeamReactome 48 Update
74955view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74599view08:38, 30 April 2014ReactomeTeamReactome46
69005view17:46, 8 July 2013MaintBotUpdated to 2013 gpml schema
42099view21:57, 4 March 2011MaintBotAutomatic update
39909view05:56, 21 January 2011MaintBotNew pathway

External references


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NameTypeDatabase referenceComment
Collagen type I fibril:vWFComplexR-HSA-114596 (Reactome)
Collagen type I fibrilR-HSA-1474201 (Reactome)
Collagen type I fibril R-HSA-1474201 (Reactome)
FCER1G ProteinP30273 (Uniprot-TrEMBL)
FCERIG dimerComplexR-HSA-210223 (Reactome)
FYN ProteinP06241 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
GP VI : FceRI gamma dimerComplexR-HSA-114575 (Reactome)
GP1BA ProteinP07359 (Uniprot-TrEMBL)
GP1BB ProteinP13224 (Uniprot-TrEMBL)
GP5 ProteinP40197 (Uniprot-TrEMBL)
GP6 ProteinQ9HCN6 (Uniprot-TrEMBL)
GP6ProteinQ9HCN6 (Uniprot-TrEMBL)
GP9 ProteinP14770 (Uniprot-TrEMBL)
GPIb-IX-VComplexR-HSA-114668 (Reactome)
GPVI:FceRI gamma:FYN:LYN:Collagen type IComplexR-HSA-434812 (Reactome)
GPVI:FceRI gamma:FYN:LYNComplexR-HSA-432297 (Reactome)
GpIb-IX-V:Collagen type I fibril:vWFComplexR-HSA-435464 (Reactome)
ITGA1 ProteinP56199 (Uniprot-TrEMBL)
ITGA10 ProteinO75578 (Uniprot-TrEMBL)
ITGA2 ProteinP17301 (Uniprot-TrEMBL)
ITGB1 ProteinP05556 (Uniprot-TrEMBL)

alpha1beta1, alpha2beta1,

ComplexR-HSA-444996 (Reactome)


alpha2beta1:Collagen type I fibril:Mg2+
ComplexR-HSA-114562 (Reactome)
LYN ProteinP07948 (Uniprot-TrEMBL)
LYNProteinP07948 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
Mg2+MetaboliteCHEBI:18420 (ChEBI)
VWF(23-763) ProteinP04275 (Uniprot-TrEMBL)
VWF(23-763)ProteinP04275 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Collagen type I fibril:vWFArrowR-HSA-114671 (Reactome)
Collagen type I fibril:vWFR-HSA-114670 (Reactome)
Collagen type I fibrilR-HSA-114563 (Reactome)
Collagen type I fibrilR-HSA-114577 (Reactome)
Collagen type I fibrilR-HSA-114671 (Reactome)
FCERIG dimerR-HSA-210282 (Reactome)
FYNR-HSA-432295 (Reactome)
GP VI : FceRI gamma dimerArrowR-HSA-210282 (Reactome)
GP VI : FceRI gamma dimerR-HSA-432295 (Reactome)
GP6R-HSA-210282 (Reactome)
GPIb-IX-VR-HSA-114670 (Reactome)
GPVI:FceRI gamma:FYN:LYN:Collagen type IArrowR-HSA-114577 (Reactome)
GPVI:FceRI gamma:FYN:LYNArrowR-HSA-432295 (Reactome)
GPVI:FceRI gamma:FYN:LYNR-HSA-114577 (Reactome)
GpIb-IX-V:Collagen type I fibril:vWFArrowR-HSA-114670 (Reactome)

alpha1beta1, alpha2beta1,

R-HSA-114563 (Reactome)


alpha2beta1:Collagen type I fibril:Mg2+
ArrowR-HSA-114563 (Reactome)
LYNR-HSA-432295 (Reactome)
Mg2+R-HSA-114563 (Reactome)
R-HSA-114563 (Reactome) Integrin alpha1beta1 binds to collagen type IV and VI with higher affinity than to types I-III, whereas alpha2beta1 has a higher affinity for collagen types I-III than for type IV. Integrin alpha10beta1 binds collagen types I, IV, and VI with similar affinities (Tulla et al. 2001). Integrin alpha11beta1 binds preferentially to the fibril-forming collagen types I and II, binding to type III is weaker and collagens IV and VI are poor ligands (Zhang et al. 2003).

Binding to collagen type I occurs at sites corresponding to the six-residue sequence G(F/L)OGER (Knight et al. 1998, 2000, Xu et al. 2000).

Integrin alpha2beta1 is the major platelet collagen receptor (Kunicki et al. 1988). It requires Mg2+ to interact with collagen and may require initiation mediated by the activation of Integrin alphaIIbBeta3 (van de Walle 2007).
R-HSA-114577 (Reactome) GPVI receptor has little affinity for soluble forms of collagen but binds collagen fibrils. Recent structural models indicate that each GPVI receptor complex could bind up to 3 collagen fibrils (Jung & Moroi 2008). The Src family kinases Fyn and Lyn constitutively associate with the GPVI-FceRIgamma complex in platelets and initiate platelet activation through phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in the FceRIgamma 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.
R-HSA-114670 (Reactome) The initial tethering of platelets at sites of vascular injury is mediated by a receptor complex of glycoproteins 1b, IX and V (GP1b-IX-V - frequently referred to as the GPIb receptor). The GP1b component binds to von Willebrand factor (vWF) complexed with collagen exposed in vascular epithelium following injury. In conditions of high shear stress, when a blood vessel is partially blocked, vWF can bind to GP1b:V:IX in tha absence of collagen, a major factor in heart attack and stroke. GPIb-IX-V interaction with vWF:collagen potentiates the ability of alphaIIb betaIII integrin to bind vWF and fibrinogen, triggering stable platelet adhesion and generation of further signals that lead to aggregation.
R-HSA-114671 (Reactome) At the beginning of this reaction, 1 molecule of 'Collagen I', and 1 molecule of 'Von Willebrand factor precursor' are present. At the end of this reaction, 1 molecule of 'Collagen IV : vWF complex' is present.

R-HSA-210282 (Reactome) Glycoprotein VI (GPVI) was identified as a collagen receptor from studies of patients with a GPVI deficiency. GPVI-deficient platelets lack collagen-induced aggregation and the ability to form thrombi on a collagen surface under flow conditions. GPVI complexes with the Fc epsilon R1 receptor gamma chain, with a possible stochiometry of two GPVI molecules and one FceRI gamma-chain dimer (Jung & Moroi 2008). GPVI binding to FcR gamma is necessary for high affinity GPVI binding to collagen.
R-HSA-432295 (Reactome) Fyn and Lyn constitutively associate with GPVI-Fc epsilon R1 gamma in platelets. The proline-rich region of GPVI is required for this interaction.
VWF(23-763)R-HSA-114671 (Reactome)
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