title: Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits low density lipoprotein-induced signaling in platelets.
abstract: 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.
authors.affiliation: Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht and the Institute for Biomembranes, University of Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Relou
authors.forename: Gertie
authors.initials: G
authors.lastname: Gorter
authors.forename: Irlando Andrade
authors.initials: IA
authors.lastname: Ferreira
authors.forename: Herman J M
authors.initials: HJ
authors.lastname: van Rijn
authors.forename: Jan-Willem N
authors.initials: JW
authors.lastname: Akkerman
mesh_terms: D020816:Amino Acid Motifs; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003600:Cytosol / Q000201:enzymology*; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry; D014638:Vanadates / Q000737:chemistry; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D003432:Cross-Linking Reagents; D008077:Lipoproteins, LDL; D010455:Peptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019319:Okadaic Acid; D013912:Threonine; D014638:Vanadates; D014443:Tyrosine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054467:Phospholipases A2; D010749:Phosphoprotein Phosphatases