GP1b-IX-V activation signaling (Homo sapiens)
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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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type I
fibril:vWF:14-3-3-zetaAnnotated Interactions
type I
fibril:vWF:14-3-3-zetatype I
fibril:vWF:14-3-3-zetatype I
fibril:vWF:14-3-3-zetaThough 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).
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).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).