GP1b-IX-V activation signaling (Homo sapiens)

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3, 124, 7, 11, 13981061, 25cytosolPIK3R1GP1BB Active c-Src:Raf1YWHAZ GP9 14-3-3-zeta:Raf1GPIb-IX-V:vWF:14-3-3-zetaGP5 GP9 VWF(23-763) p-Y419-SRC GP1BA GP5 FLNAGP5 RAF1 GP1BB GP9 YWHAZ GP1BB VWF(23-763) GP5 GPIb-IX-V:vWF:14-3-3-zeta:p85GP1BA YWHAZ PIK3R1 GPIb-IX-V:vWF:filamin-AGP1BA GP1BA VWF(23-763) RAF1 YWHAZ GPIb-IX-V:vWF14-3-3zeta dimerFLNA SRC-1GP1BB VWF(23-763) GP9 p-Y419-SRCRAF1


Description

The platelet GPIb complex (GP1b-IX-V) together with GPVI are primarily responsible for regulating the initial adhesion of platelets to the damaged blood vessel and platelet activation. The importance of GPIb is demonstrated by the bleeding problems in patients with Bernard-Soulier syndrome where this receptor is either absent or defective. GP1b-IX-V binds von Willebrand Factor (vWF) to resting platelets, particularly under conditions of high shear stress. This transient interaction is the first stage of the vascular repair process. Activation of GP1b-IX-V on exposure of the fibrous matrix following atherosclerotic plaque rupture, or in occluded arteries, is a major contributory factor leading to thrombus formation leading to heart attack or stroke.

GpIb also binds thrombin (Yamamoto et al. 1986), at a site distinct from the site of vWF binding, acting as a docking site for thrombin which then activates Proteinase Activated Receptors leading to enhanced platelet activation (Dormann et al. 2000).

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Bibliography

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  1. Feng S, Christodoulides N, Reséndiz JC, Berndt MC, Kroll MH.; ''Cytoplasmic domains of GpIbalpha and GpIbbeta regulate 14-3-3zeta binding to GpIb/IX/V.''; PubMed Europe PMC Scholia
  2. Munday AD, Berndt MC, Mitchell CA.; ''Phosphoinositide 3-kinase forms a complex with platelet membrane glycoprotein Ib-IX-V complex and 14-3-3zeta.''; PubMed Europe PMC Scholia
  3. Andrews RK, Harris SJ, McNally T, Berndt MC.; ''Binding of purified 14-3-3 zeta signaling protein to discrete amino acid sequences within the cytoplasmic domain of the platelet membrane glycoprotein Ib-IX-V complex.''; PubMed Europe PMC Scholia
  4. Okita JR, Pidard D, Newman PJ, Montgomery RR, Kunicki TJ.; ''On the association of glycoprotein Ib and actin-binding protein in human platelets.''; PubMed Europe PMC Scholia
  5. Fantl WJ, Muslin AJ, Kikuchi A, Martin JA, MacNicol AM, Gross RW, Williams LT.; ''Activation of Raf-1 by 14-3-3 proteins.''; PubMed Europe PMC Scholia
  6. Ruggeri ZM, Mendolicchio GL.; ''Adhesion mechanisms in platelet function.''; PubMed Europe PMC Scholia
  7. Andrews RK, Berndt MC.; ''Platelet physiology and thrombosis.''; PubMed Europe PMC Scholia
  8. Du X, Fox JE, Pei S.; ''Identification of a binding sequence for the 14-3-3 protein within the cytoplasmic domain of the adhesion receptor, platelet glycoprotein Ib alpha.''; PubMed Europe PMC Scholia
  9. Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I.; ''The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress.''; PubMed Europe PMC Scholia
  10. Cleghon V, Morrison DK.; ''Raf-1 interacts with Fyn and Src in a non-phosphotyrosine-dependent manner.''; PubMed Europe PMC Scholia
  11. Du X, Harris SJ, Tetaz TJ, Ginsberg MH, Berndt MC.; ''Association of a phospholipase A2 (14-3-3 protein) with the platelet glycoprotein Ib-IX complex.''; PubMed Europe PMC Scholia
  12. Williamson D, Pikovski I, Cranmer SL, Mangin P, Mistry N, Domagala T, Chehab S, Lanza F, Salem HH, Jackson SP.; ''Interaction between platelet glycoprotein Ibalpha and filamin-1 is essential for glycoprotein Ib/IX receptor anchorage at high shear.''; PubMed Europe PMC Scholia
  13. Ozaki Y, Asazuma N, Suzuki-Inoue K, Berndt MC.; ''Platelet GPIb-IX-V-dependent signaling.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
116423view09:11, 7 May 2021EweitzModified title
114766view16:25, 25 January 2021ReactomeTeamReactome version 75
113210view11:27, 2 November 2020ReactomeTeamReactome version 74
112434view15:38, 9 October 2020ReactomeTeamReactome version 73
101339view11:22, 1 November 2018ReactomeTeamreactome version 66
100877view20:56, 31 October 2018ReactomeTeamreactome version 65
100418view19:30, 31 October 2018ReactomeTeamreactome version 64
99968view16:14, 31 October 2018ReactomeTeamreactome version 63
99522view14:49, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93846view13:40, 16 August 2017ReactomeTeamreactome version 61
93403view11:22, 9 August 2017ReactomeTeamreactome version 61
87456view14:03, 22 July 2016MkutmonOntology Term : 'hemostasis pathway' added !
86489view09:19, 11 July 2016ReactomeTeamreactome version 56
83423view11:11, 18 November 2015ReactomeTeamVersion54
81626view13:10, 21 August 2015ReactomeTeamVersion53
77086view08:38, 17 July 2014ReactomeTeamFixed remaining interactions
76792view12:17, 16 July 2014ReactomeTeamFixed remaining interactions
76115view10:18, 11 June 2014ReactomeTeamRe-fixing comment source
75827view11:39, 10 June 2014ReactomeTeamReactome 48 Update
75188view09:38, 9 May 2014AnweshaFixing comment source for displaying WikiPathways description
74828view10:05, 30 April 2014ReactomeTeamReactome46
42046view21:52, 4 March 2011MaintBotAutomatic update
39849view05:52, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14-3-3-zeta:Raf1ComplexR-HSA-443827 (Reactome)
14-3-3zeta dimerComplexR-HSA-206751 (Reactome)
Active c-Src:Raf1ComplexR-HSA-443443 (Reactome)
FLNA ProteinP21333 (Uniprot-TrEMBL)
FLNAProteinP21333 (Uniprot-TrEMBL)
GP1BA ProteinP07359 (Uniprot-TrEMBL)
GP1BB ProteinP13224 (Uniprot-TrEMBL)
GP5 ProteinP40197 (Uniprot-TrEMBL)
GP9 ProteinP14770 (Uniprot-TrEMBL)
GPIb-IX-V:vWF:14-3-3-zeta:p85ComplexR-HSA-443399 (Reactome)
GPIb-IX-V:vWF:14-3-3-zetaComplexR-HSA-429544 (Reactome)
GPIb-IX-V:vWF:filamin-AComplexR-HSA-430104 (Reactome)
GPIb-IX-V:vWFComplexR-HSA-429541 (Reactome)
PIK3R1 ProteinP27986 (Uniprot-TrEMBL)
PIK3R1ProteinP27986 (Uniprot-TrEMBL)
RAF1 ProteinP04049 (Uniprot-TrEMBL)
RAF1ProteinP04049 (Uniprot-TrEMBL)
SRC-1ProteinP12931-1 (Uniprot-TrEMBL)
VWF(23-763) ProteinP04275 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
p-Y419-SRC ProteinP12931-1 (Uniprot-TrEMBL)
p-Y419-SRCProteinP12931-1 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
14-3-3-zeta:Raf1ArrowR-HSA-443831 (Reactome)
14-3-3zeta dimerArrowR-HSA-430073 (Reactome)
14-3-3zeta dimerR-HSA-430076 (Reactome)
14-3-3zeta dimerR-HSA-443831 (Reactome)
Active c-Src:Raf1ArrowR-HSA-443439 (Reactome)
FLNAR-HSA-430096 (Reactome)
GPIb-IX-V:vWF:14-3-3-zeta:p85ArrowR-HSA-443402 (Reactome)
GPIb-IX-V:vWF:14-3-3-zetaArrowR-HSA-430076 (Reactome)
GPIb-IX-V:vWF:14-3-3-zetaR-HSA-430073 (Reactome)
GPIb-IX-V:vWF:14-3-3-zetaR-HSA-443402 (Reactome)
GPIb-IX-V:vWF:filamin-AArrowR-HSA-430096 (Reactome)
GPIb-IX-V:vWFArrowR-HSA-430073 (Reactome)
GPIb-IX-V:vWFR-HSA-430076 (Reactome)
GPIb-IX-V:vWFR-HSA-430096 (Reactome)
GPIb-IX-V:vWFR-HSA-443418 (Reactome)
PIK3R1R-HSA-443402 (Reactome)
R-HSA-430073 (Reactome) High shear stress, or immobilization of VWF under high shear conditions induce VWF binding to GPIb-IX-V. This activation mechanism is believed to involve shear-stress induced conformational changes in vWF.
R-HSA-430076 (Reactome) The Gp1b-IX-V complex binds to 14-3-3-zeta, a scaffolding protein. The highly conserved cytoplasmic domain of GpIb alpha binds directly to dimeric 14-3-3 zeta adapter protein. Binding also involves regions of GpV, and is enhanced by phosphorylation of GP1b at Ser-609 or Ser-166 of Gp1b alpha and beta respectively. For Gp1b beta this phosphorylation is PKA-dependent.
R-HSA-430096 (Reactome) GP1b-IX-V interacts with filamin-1; within the cytoplasmic domain of GP1b alpha amino acids 557-568 and 569-579 are critical for this association. GPIb-filamin-1 association links the receptor complex to the membrane skeleton and has been proposed to regulate the ability of GPIb-IX-V to adhere to vWf under conditions of high shear.
R-HSA-443402 (Reactome) Resting platelets contain a heterotrimeric complex of GPIb-IX-V, 14-3-3-zeta and the p85 subunit of PI-3K. While GPIb-IX-V has no apparent binding sites for PI3K so the interaction with p85 is likely to be mediated by 14-3-3-zeta.
R-HSA-443418 (Reactome) Src and its downstream signaling molecule PLC gamma 2 are implicated in GPIb-IX-V (GPIbR) signalling. GPIbR-mediated platelet activation correlates with cytoskeletal association of Src, activation of PI3K and the appearance of multiple tyrosine-phosphorylated proteins (Jackson et al. 1994). von Willebrand Factor (vWF) and the vWF modulator botrocetin induce tyrosine phosphorylation of FceRIgamma, Syk, LAT and PLCgamma2. Src kinase inhibition markedly suppresses these events (Wu et al. 2001). Src and Lyn form a complex with FceRIgamma and Syk upon GPIbR/vWF interaction (Wu et al. 2003). FcgammaRIIa was tyrosine phosphorylated upon vWF and ristocetin-induced-platelet activation, followed by Syk and PLCgamma2 activation. A selective Src kinase inhibitor inhibited these events (Torti et al. 1994).

Though a considerable body of evidence suggests Src as a signaling molecule downstream of GPIbR the mechanism that connects Src to GPIbR is not clear. There are obvious similarities with the GPIV signal transduction pathway but also important differences: Src appears to be recruited to GPIbR upon platelet activation, while Lyn and Fyn constitutively associate with GPVI; GPVI activation induces a robust level of inositol phosphate production and PLCgamma2 activity, while GPIbRactivation PLCgamma2 activation is modest and the tyrosine phosphorylation sites of PLCgamma2 are distinct from those of GPVI stimulation (Suzuki-Inoue et al. 2004). GPVI signalling requires the FCeRIgamma chain while mouse knockouts suggest it is not required for GPIbR signalling (Kaiser-Friede et al. 2004).
Studies on GPIbalpha transgenic mice suggested that GPIbR activates AlphaIIbBeta3 Integrin through Src and PLC gamma2 activation (Kaiser-Friede et al. 2004). An alternative suggested mechansim is indirect association via 14-3-3-zeta and the p85 subunit of PI3K; the p85 subunit of PI3K constitutively associates with GPIbR so upon vWF/GPIb-IX-V interaction can bind Src via its SH3 domain (Wu et al. 2003).

Although many studies support a role for Src signaling in vWF/GPIb induced platelet activation, Src-independent platelet activation has been reported for platelets spreading on surfaces coated with echicetin, a GPIb-cross-linking component of snake venom (Navdaev & Clemetson, 2002).
R-HSA-443439 (Reactome) c-Src binds to Raf1, the interaction involves the SH2 and SH3 domains of c-Src and requires serine phosphorylation of Raf1. Coexpression of Raf1 and c-Src in Sf9 cells results in c-Src/Raf-1 complexes, tyrosine phosphorylation of Raf-1, and stimulation of Raf-1 kinase activity. Tyr-340 and Tyr-341 were found to be the major tyrosine phosphorylation sites of Raf1 when coexpressed with activated tyrosine kinases. However, the significance of tyrosine phosphorylation under physiological conditions remains unclear, as tyrosine phosphorylation of endogenous Raf-1 following activation has been disputed and may be limited to cells of hematopoietic origin.
R-HSA-443831 (Reactome) 14-3-3 family proteins can bind Raf1 and have been suggested to activate Raf1, but this has been refuted.
RAF1R-HSA-443439 (Reactome)
RAF1R-HSA-443831 (Reactome)
SRC-1R-HSA-443418 (Reactome)
p-Y419-SRCArrowR-HSA-443418 (Reactome)
p-Y419-SRCR-HSA-443439 (Reactome)
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