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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. J Thromb Haemost 2010 Nov;8(11):2530-41

Date

08/21/2010

Pubmed ID

20723025

Pubmed Central ID

PMC3298659

DOI

10.1111/j.1538-7836.2010.04025.x

Scopus ID

2-s2.0-78149258905 (requires institutional sign-in at Scopus site)   41 Citations

Abstract

BACKGROUND: 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. 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-FcRγ-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.

Author List

Moraes LA, Barrett NE, Jones CI, Holbrook LM, Spyridon M, Sage T, Newman DK, Gibbins JM

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Animals
Blood Platelets
Class Ia Phosphatidylinositol 3-Kinase
Collagen
GRB2 Adaptor Protein
Humans
Membrane Proteins
Mice
Phosphatidylinositol 3-Kinases
Phosphoproteins
Phosphorylation
Platelet Activation
Platelet Endothelial Cell Adhesion Molecule-1
Platelet Membrane Glycoproteins
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Signal Transduction
Tyrosine