title: PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets.
abstract: Platelet adhesion at sites of vascular injury is mediated, in part, by interaction of the platelet plasma membrane glycoprotein (GP) Ib/V/IX complex with von Willebrand Factor (VWF) presented on collagen-exposed surfaces. Recent studies indicate that GPIb/V/IX may be functionally coupled with the Fc receptor gamma (FcR gamma)-chain, which, by virtue of its cytoplasmic immunoreceptor tyrosine-based activation motif, sends activation signals into the cell. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an inhibitory receptor that has previously been shown to negatively regulate platelet responses to collagen, which transduces activation signals via the GPVI/FcR gamma-chain complex. To determine whether PECAM-1 might similarly regulate signals emanating from GPIb/FcR gamma, we compared activation and aggregation responses to VWF of PECAM-1-positive and PECAM-1-deficient murine platelets. PECAM-1 and the FcR gamma-chain became rapidly tyrosine phosphorylated in platelets following botrocetin-induced VWF binding, but FcR gamma-chain tyrosine phosphorylation was delayed in PECAM-1-positive, versus PECAM-1-deficient, platelets. PECAM-1-deficient platelets were hyperaggregable to VWF, exhibited enhanced spreading and, under conditions of arterial flow, formed markedly larger thrombi on immobilized VWF than did wild-type platelets. Taken together, these data support the notion that engagement of the GPIb complex, in addition to sending activation signals, also initiates a negative feedback loop involving PECAM-1 that controls the rate and extent of platelet activation.
authors.affiliation: Blood Research Institute, The Blood Center of Southeastern Wisconsin, PO Box 2178, 638 N 18th St, Milwaukee, WI 53201, USA. vrathore@bcsew.edu
authors.forename: Vipul
authors.initials: V
authors.lastname: Rathore
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Stapleton
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hillery
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.forename: Debra K
authors.initials: DK
authors.lastname: Newman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Newman
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015539:Platelet Activation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism; D015398:Signal Transduction; D013927:Thrombosis / Q000209:etiology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D017452:Receptors, IgG; D014841:von Willebrand Factor