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Blood, 15 November 2003, Vol. 102, No. 10, pp. 3658-3664.
Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-06-1888.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets
Vipul Rathore,
Michelle A. Stapleton,
Cheryl A. Hillery,
Robert R. Montgomery,
Timothy C. Nichols,
Elizabeth P. Merricks,
Debra K. Newman, and
Peter J. Newman
From the Blood Research Institute, The Blood Center of Southeastern Wisconsin, Milwaukee; the Cardiovascular Center and the Departments of Pediatrics, Microbiology, Pharmacology, and Cellular Biology, Medical College of Wisconsin, Milwaukee; and the Department of Pathology and Laboratory Medicine, The School of Medicine, University of North Carolina at Chapel Hill.
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  (FcR)-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-chain complex. To determine whether PECAM-1 might similarly regulate signals emanating from GPIb/FcR, we compared activation and aggregation responses to VWF of PECAM-1-positive and PECAM-1-deficient murine platelets. PECAM-1 and the FcR-chain became rapidly tyrosine phosphorylated in platelets following botrocetin-induced VWF binding, but FcR-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. (Blood. 2003;102:3658-3664)
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