Platelet endothelial cell adhesion molecule-1 regulates collagen-stimulated platelet function by modulating the association of phosphatidylinositol 3-kinase with Grb-2-associated binding protein-1 and linker for activation of T cells.
Bottom Line: Platelet activation by collagen depends on signals transduced by the glycoprotein (GP)VI-Fc receptor (FcR)γ-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.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.
Affiliation: Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK. email@example.comShow MeSH
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Mentions: Our working model (Fig. 5) shows that the activation of platelets results in PECAM-1 phosphorylation and signaling, providing negative feedback to activation pathways. Collagen stimulation of platelets results in the formation of a complex between PI3K and the adaptor protein Gab1, which also binds to LAT, forming a signaling complex. Gab1 also interacts with SHP-2, another component capable of joining this complex, in collagen-stimulated platelets, and this interaction is enhanced in the absence of PECAM-1 signaling. The stimulation of PECAM-1 results in the recruitment of p85 to PECAM-1, and enhances the ability of SHP-2 to interact with p85. The ability in vitro of SHP-2 to directly interact with p85 supports the notion that the interaction of p85 with PECAM-1 is mediated indirectly by the phosphatase. Furthermore, the substantial reduction in the interaction between SHP-2 and p85 in the absence of PECAM-1 suggests that PECAM-1 controls this association. Consistent with what has been found for other cell types , our model highlights the ability of PECAM-1 to modulate the assembly of the LAT signalosome, where PECAM-1 activation and SHP-2 recruitment result in diminished association of the p85 subunit of PI3K with Gab1 and LAT, moving p85 from a substrate-rich to a substrate-poor environment (80% of PECAM-1 is excluded from lipid rafts) . This would lead to a redistribution of p85 from LAT-containing lipid raft compartments to PECAM-1 signaling complexes, causing a reduction in collagen-mediated signaling through relocation of the enzyme away from the activated collagen receptor complex.
Affiliation: Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK. firstname.lastname@example.org