Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 8, Issue 11, Pages 2530-2541Publisher
WILEY
DOI: 10.1111/j.1538-7836.2010.04025.x
Keywords
GPVI; inhibitory; ITIM; PECAM-1; signaling
Categories
Funding
- British Heart Foundation [RG/05/007]
- Heart Research UK [RG2543/07/10]
- Wellcome Trust [082338/Z/07/Z]
- Medical Research Council UK
- NIH, USA [R01HL090883, HL044612]
- Wellcome Trust [082338/Z/07/Z] Funding Source: Wellcome Trust
- British Heart Foundation [RG/09/011/28094] Funding Source: researchfish
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Background: Platelet activation by collagen depends on signals transduced by the glycoprotein (GP)VI-Fc receptor (FcR)gamma-chain collagen receptor complex, which involves recruitment of phosphatidylinositol 3-kinase (PI3K) to phosphorylated tyrosines in the linker for activation of T cells (LAT). An interaction between the p85 regulatory subunit of PI3K and the scaffolding molecule Grb-2-associated binding protein-1 (Gab1), which is regulated by binding of the Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) to Gab1, has been shown in other cell types to sustain PI3K activity to elicit cellular responses. Platelet endothelial cell adhesion molecule-1 (PECAM-1) functions as a negative regulator of platelet reactivity and thrombosis, at least in part by inhibiting GPVI-FcR gamma-chain signaling via recruitment of SHP-2 to phosphorylated immunoreceptor tyrosine-based inhibitory motifs in PECAM-1. Objective: To investigate the possibility that PECAM-1 regulates the formation of the Gab1-p85 signaling complexes, and the potential effect of such interactions on GPVI-mediated platelet activation in platelets. Methods: The ability of PECAM-1 signaling to modulate the LAT signalosome was investigated with immunoblotting assays on human platelets and knockout mouse platelets. Results: PECAM-1-associated SHP-2 in collagen-stimulated platelets binds to p85, which results in diminished levels of association with both Gab1 and LAT and reduced collagen-stimulated PI3K signaling. We therefore propose that PECAM-1-mediated inhibition of GPVI-dependent platelet responses result, at least in part, from recruitment of SHP-2-p85 complexes to tyrosine-phosphorylated PECAM-1, which diminishes the association of PI3K with activatory signaling molecules, such as Gab1 and LAT.
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