GP1b-IX-V activation signaling (Homo sapiens)

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Bibliography

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

External references

DataNodes

Name	Type	Database reference	Comment
14-3-3-zeta:Raf1	Complex	REACT_24804 (Reactome)
14-3-3zeta dimer	Complex	REACT_24853 (Reactome)
Active c-Src:Raf1	Complex	REACT_24303 (Reactome)
FLNA [cytosol]	Protein	P21333 (Uniprot-TrEMBL)
FLNA	Protein	P21333 (Uniprot-TrEMBL)
GP1BA [plasma membrane]	Protein	P07359 (Uniprot-TrEMBL)
GP1BB [plasma membrane]	Protein	P13224 (Uniprot-TrEMBL)
GP5 [plasma membrane]	Protein	P40197 (Uniprot-TrEMBL)
GP9 [plasma membrane]	Protein	P14770 (Uniprot-TrEMBL)
GPIb-IX-V:vWF:14-3-3-zeta:p85	Complex	REACT_24633 (Reactome)
GPIb-IX-V:vWF:14-3-3-zeta	Complex	REACT_24215 (Reactome)
GPIb-IX-V:vWF:filamin-A	Complex	REACT_24471 (Reactome)
GPIb-IX-V:vWF	Complex	REACT_24749 (Reactome)
PIK3R1 [cytosol]	Protein	P27986 (Uniprot-TrEMBL)
PIK3R1	Protein	P27986 (Uniprot-TrEMBL)
RAF1 [cytosol]	Protein	P04049 (Uniprot-TrEMBL)
RAF1	Protein	P04049 (Uniprot-TrEMBL)
SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)
VWF(23-763) [extracellular region]	Protein	P04275 (Uniprot-TrEMBL)
YWHAZ [cytosol]	Protein	P63104 (Uniprot-TrEMBL)
p-Y419-SRC-1 [cytosol]	Protein	P12931-1 (Uniprot-TrEMBL)
p-Y419-SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	14-3-3-zeta:Raf1	Arrow	REACT_23766 (Reactome)
	14-3-3zeta dimer	Arrow	REACT_23970 (Reactome)
14-3-3zeta dimer			REACT_23766 (Reactome)
14-3-3zeta dimer			REACT_23993 (Reactome)
	Active c-Src:Raf1	Arrow	REACT_23808 (Reactome)
FLNA			REACT_23834 (Reactome)
	GPIb-IX-V:vWF:14-3-3-zeta:p85	Arrow	REACT_23952 (Reactome)
	GPIb-IX-V:vWF:14-3-3-zeta	Arrow	REACT_23993 (Reactome)
GPIb-IX-V:vWF:14-3-3-zeta			REACT_23952 (Reactome)
GPIb-IX-V:vWF:14-3-3-zeta			REACT_23970 (Reactome)
	GPIb-IX-V:vWF:filamin-A	Arrow	REACT_23834 (Reactome)
	GPIb-IX-V:vWF	Arrow	REACT_23970 (Reactome)
GPIb-IX-V:vWF			REACT_23834 (Reactome)
GPIb-IX-V:vWF			REACT_23993 (Reactome)
GPIb-IX-V:vWF			REACT_24010 (Reactome)
PIK3R1			REACT_23952 (Reactome)
RAF1			REACT_23766 (Reactome)
RAF1			REACT_23808 (Reactome)
			REACT_23766 (Reactome)	14-3-3 family proteins can bind Raf1 and have been suggested to activate Raf1, but this has been refuted.
			REACT_23808 (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.
			REACT_23834 (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.
			REACT_23952 (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.
			REACT_23970 (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.
			REACT_23993 (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.
			REACT_24010 (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).
SRC-1			REACT_24010 (Reactome)
	p-Y419-SRC-1	Arrow	REACT_24010 (Reactome)
p-Y419-SRC-1			REACT_23808 (Reactome)