Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits low density lipoprotein-induced signaling in platelets.
At physiological concentrations, low density lipoprotein (LDL) increases the sensitivity of platelets to aggregation- and secretion-inducing agents without acting as an independent activator of platelet functions. LDL sensitizes platelets by inducing a transient activation of p38MAPK, a Ser/Thr kinase that is activated by the simultaneous phosphorylation of Thr180 and Tyr182 ... and is an upstream regulator of cytosolic phospholipase A2 (cPLA2). A similar transient phosphorylation of p38MAPK is induced by a peptide mimicking amino acids 3359-3369 in apoB100 called the B-site. Here we report that the transient nature of p38MAPK activation is caused by platelet endothelial cell adhesion molecule 1 (PECAM-1), a receptor with an immunoreceptor tyrosine-based inhibitory motif. PECAM-1 activation by cross-linking induces tyrosine phosphorylation of PECAM-1 and a fall in phosphorylated p38MAPK and cPLA2. Interestingly, LDL and the B-site peptide also induce tyrosine phosphorylation of PECAM-1, and studies with immunoprecipitates indicate the involvement of c-Src. Inhibition of the Ser/Thr phosphatases PP1/PP2A (okadaic acid) makes the transient p38MAPK activation by LDL and the B-site peptide persistent. Inhibition of Tyr-phosphatases (vanadate) increases Tyr-phosphorylated PECAM-1 and blocks the activation of p38MAPK. Together, these findings suggest that, following a first phase in which LDL, through its B-site, phosphorylates and thereby activates p38MAPK, a second phase is initiated in which LDL activates PECAM-1 and induces dephosphorylation of p38MAPK via activation of the Ser/Thr phosphatases PP1/PP2A.
Mesh Terms:
Amino Acid Motifs, Antigens, CD31, Blood Platelets, Blotting, Western, Cross-Linking Reagents, Cytosol, Down-Regulation, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Humans, Lipoproteins, LDL, Mitogen-Activated Protein Kinases, Okadaic Acid, Peptides, Phospholipases A, Phospholipases A2, Phosphoprotein Phosphatases, Phosphorylation, Signal Transduction, Threonine, Time Factors, Tyrosine, Vanadates, p38 Mitogen-Activated Protein Kinases
Amino Acid Motifs, Antigens, CD31, Blood Platelets, Blotting, Western, Cross-Linking Reagents, Cytosol, Down-Regulation, Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Humans, Lipoproteins, LDL, Mitogen-Activated Protein Kinases, Okadaic Acid, Peptides, Phospholipases A, Phospholipases A2, Phosphoprotein Phosphatases, Phosphorylation, Signal Transduction, Threonine, Time Factors, Tyrosine, Vanadates, p38 Mitogen-Activated Protein Kinases
J. Biol. Chem.
Date: Aug. 29, 2003
PubMed ID: 12775720
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