Faculty Collaboration Database

PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood 2003 Nov 15;102(10):3658-64

Date

08/02/2003

Pubmed ID

12893757

DOI

10.1182/blood-2003-06-1888

Scopus ID

2-s2.0-0242411524 (requires institutional sign-in at Scopus site)   79 Citations

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.

Author List

Rathore V, Stapleton MA, Hillery CA, Montgomery RR, Nichols TC, Merricks EP, Newman DK, Newman PJ

Authors

Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of Wisconsin
Debra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Down-Regulation
Humans
Mice
Mice, Knockout
Phosphorylation
Platelet Activation
Platelet Endothelial Cell Adhesion Molecule-1
Platelet Glycoprotein GPIIb-IIIa Complex
Platelet Glycoprotein GPIb-IX Complex
Receptors, IgG
Signal Transduction
Thrombosis
von Willebrand Factor