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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.

Moraes LA, Barrett NE, Jones CI, Holbrook LM, Spyridon M, Sage T, Newman DK, Gibbins JM - J. Thromb. Haemost. (2010)

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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK. l.a.moraes@reading.ac.uk

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Working model for the modulation of collagen-stimulated phosphatidylinositol 3-kinase (PI3K) signaling and platelet function by platelet endothelial cell adhesion molecule-1 (PECAM-1). Homophilic ligand binding or clustering of PECAM-1 or glycoprotein (GP)VI activation by collagen results in stimulation of tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motifs present in the cytoplasmic tail of PECAM-1. This results in the recruitment and activation of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2). Collagen stimulation of platelets results in the formation of a complex between PI3K and the adaptor protein Grb-2-associated binding protein-1 (Gab1), which also binds to linker for activation of T cells (LAT), forming a signaling complex. SHP-2 is also capable of joining this complex, an interaction that is enhanced in the absence of PECAM-1 signaling. The stimulation of PECAM-1 results in the recruitment of p85 to bind to PECAM-1. The ability in vitro of SHP-2 to directly interact with p85 suggests that the interaction of p85 and PECAM-1 is mediated indirectly by the phosphatase. Indeed, the interaction between SHP-2 and p85 is dramatically reduced in the absence of PECAM-1, suggesting that PECAM-1 controls this interaction. Consistent with studies in another cell types where SHP-2 disrupts Gab1 and p85 interactions, through dephosphorylation of a tyrosine required for binding, the absence of PECAM-1 results in stabilization of the interaction between Gab1 and p85. This indicates that PECAM-1 signaling results in the loss of PI3K from the LAT signalosome and reduced levels of PI3K signaling. The relative redistribution of p85 from the LAT signalosome may be correlated with the inhibition of PI3K signaling. This provides a mechanism by which the activation of PECAM-1 results in negative feedback to activation pathways. GEM, glycolipid-enriched membrane; Syk, spleen tyrosine kinase.
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fig05: Working model for the modulation of collagen-stimulated phosphatidylinositol 3-kinase (PI3K) signaling and platelet function by platelet endothelial cell adhesion molecule-1 (PECAM-1). Homophilic ligand binding or clustering of PECAM-1 or glycoprotein (GP)VI activation by collagen results in stimulation of tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motifs present in the cytoplasmic tail of PECAM-1. This results in the recruitment and activation of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2). Collagen stimulation of platelets results in the formation of a complex between PI3K and the adaptor protein Grb-2-associated binding protein-1 (Gab1), which also binds to linker for activation of T cells (LAT), forming a signaling complex. SHP-2 is also capable of joining this complex, an interaction that is enhanced in the absence of PECAM-1 signaling. The stimulation of PECAM-1 results in the recruitment of p85 to bind to PECAM-1. The ability in vitro of SHP-2 to directly interact with p85 suggests that the interaction of p85 and PECAM-1 is mediated indirectly by the phosphatase. Indeed, the interaction between SHP-2 and p85 is dramatically reduced in the absence of PECAM-1, suggesting that PECAM-1 controls this interaction. Consistent with studies in another cell types where SHP-2 disrupts Gab1 and p85 interactions, through dephosphorylation of a tyrosine required for binding, the absence of PECAM-1 results in stabilization of the interaction between Gab1 and p85. This indicates that PECAM-1 signaling results in the loss of PI3K from the LAT signalosome and reduced levels of PI3K signaling. The relative redistribution of p85 from the LAT signalosome may be correlated with the inhibition of PI3K signaling. This provides a mechanism by which the activation of PECAM-1 results in negative feedback to activation pathways. GEM, glycolipid-enriched membrane; Syk, spleen tyrosine kinase.

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 [38], 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) [49]. 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.


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.

Moraes LA, Barrett NE, Jones CI, Holbrook LM, Spyridon M, Sage T, Newman DK, Gibbins JM - J. Thromb. Haemost. (2010)

Working model for the modulation of collagen-stimulated phosphatidylinositol 3-kinase (PI3K) signaling and platelet function by platelet endothelial cell adhesion molecule-1 (PECAM-1). Homophilic ligand binding or clustering of PECAM-1 or glycoprotein (GP)VI activation by collagen results in stimulation of tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motifs present in the cytoplasmic tail of PECAM-1. This results in the recruitment and activation of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2). Collagen stimulation of platelets results in the formation of a complex between PI3K and the adaptor protein Grb-2-associated binding protein-1 (Gab1), which also binds to linker for activation of T cells (LAT), forming a signaling complex. SHP-2 is also capable of joining this complex, an interaction that is enhanced in the absence of PECAM-1 signaling. The stimulation of PECAM-1 results in the recruitment of p85 to bind to PECAM-1. The ability in vitro of SHP-2 to directly interact with p85 suggests that the interaction of p85 and PECAM-1 is mediated indirectly by the phosphatase. Indeed, the interaction between SHP-2 and p85 is dramatically reduced in the absence of PECAM-1, suggesting that PECAM-1 controls this interaction. Consistent with studies in another cell types where SHP-2 disrupts Gab1 and p85 interactions, through dephosphorylation of a tyrosine required for binding, the absence of PECAM-1 results in stabilization of the interaction between Gab1 and p85. This indicates that PECAM-1 signaling results in the loss of PI3K from the LAT signalosome and reduced levels of PI3K signaling. The relative redistribution of p85 from the LAT signalosome may be correlated with the inhibition of PI3K signaling. This provides a mechanism by which the activation of PECAM-1 results in negative feedback to activation pathways. GEM, glycolipid-enriched membrane; Syk, spleen tyrosine kinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig05: Working model for the modulation of collagen-stimulated phosphatidylinositol 3-kinase (PI3K) signaling and platelet function by platelet endothelial cell adhesion molecule-1 (PECAM-1). Homophilic ligand binding or clustering of PECAM-1 or glycoprotein (GP)VI activation by collagen results in stimulation of tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motifs present in the cytoplasmic tail of PECAM-1. This results in the recruitment and activation of the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2). Collagen stimulation of platelets results in the formation of a complex between PI3K and the adaptor protein Grb-2-associated binding protein-1 (Gab1), which also binds to linker for activation of T cells (LAT), forming a signaling complex. SHP-2 is also capable of joining this complex, an interaction that is enhanced in the absence of PECAM-1 signaling. The stimulation of PECAM-1 results in the recruitment of p85 to bind to PECAM-1. The ability in vitro of SHP-2 to directly interact with p85 suggests that the interaction of p85 and PECAM-1 is mediated indirectly by the phosphatase. Indeed, the interaction between SHP-2 and p85 is dramatically reduced in the absence of PECAM-1, suggesting that PECAM-1 controls this interaction. Consistent with studies in another cell types where SHP-2 disrupts Gab1 and p85 interactions, through dephosphorylation of a tyrosine required for binding, the absence of PECAM-1 results in stabilization of the interaction between Gab1 and p85. This indicates that PECAM-1 signaling results in the loss of PI3K from the LAT signalosome and reduced levels of PI3K signaling. The relative redistribution of p85 from the LAT signalosome may be correlated with the inhibition of PI3K signaling. This provides a mechanism by which the activation of PECAM-1 results in negative feedback to activation pathways. GEM, glycolipid-enriched membrane; Syk, spleen tyrosine kinase.
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 [38], 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) [49]. 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.

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.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cardiovascular & Metabolic Research, School of Biological Sciences, University of Reading, Reading, UK. l.a.moraes@reading.ac.uk

Show MeSH
Related in: MedlinePlus