An antibody to a platelet integral membrane glycoprotein was found to cross-react with the previously identified CD31 myelomonocytic differentiation antigen and with hec7, an endothelial cell protein that is enriched at intercellular junctions. This antibody identified a complementary DNA clone from an endothelial cell library. The 130-kilodalton translated sequence contained six extracellular immunoglobulin (Ig)-like domains and was most similar to the cell adhesion molecule (CAM) subgroup of the Ig superfamily. This is the only known member of the CAM family on platelets. Its cell surface distribution suggests participation in cellular recognition events.

The major platelet integrin, ␣IIb␤3, is required for platelet interactions with proteins in plasma and the extracellular matrices (ECMs) that are essential for platelet adhesion and aggregation during hemostasis and arterial thrombosis. Ligand binding to ␣IIb␤3 is controlled by insideout signals that modulate receptor conformation and clustering. In turn, ligand binding triggers outside-in signals through ␣IIb␤3 that, when disrupted, can cause a bleeding diathesis. In the past 5 years there has been an explosion of knowledge about the structure and function of ␣IIb␤3 and the related integrin, ␣V␤3. These developments are discussed here, and current models of bidirectional ␣IIb␤3 signaling are presented as frameworks for future investigations. An understanding that ␣IIb␤3 functions as a dynamic molecular scaffold for extracellular and intracellular proteins has translated into diagnostic and therapeutic insights relevant to hematology and cardiovascular medicine, and further advances can be anticipated. ( IntroductionThe platelet is a tightly regulated adhesion machine. Restrained in its functions while in the bloodstream, its adhesive, hemostatic, and proinflammatory capabilities are unleashed at sites of vessel injury to generate the primary hemostatic plug, catalyze fibrin formation, and supply soluble and membrane-bound factors that promote wound healing. 1 While platelets can adhere to damaged endothelial cells, 2 their principle adhesive surface is the extracellular matrix (ECM), which becomes exposed in injured vessels and offers a panoply of ligands for platelet adhesion receptors. 3 Within this context, integrin adhesion receptors, and ␣IIb␤3 in particular, play critical roles in platelet function.Integrins are heterodimeric (␣␤) type I transmembrane receptors, each subunit typically containing a relatively large extracellular domain, a single-pass transmembrane domain, and a short cytoplasmic tail composed of 20 to 60 amino acids. 4 Platelets express several integrins (␣IIb␤3, also called glycoprotein IIb-IIIa [GPIIb-IIIa]; ␣V␤3; ␣2␤1; ␣5␤1; ␣6␤1). Integrins are, in effect, "2-faced" receptors, one face oriented to the extracellular space and interactive with cognate ECM ligands and the other oriented to the cell interior and interactive with cytoplasmic proteins. Ligand binding to either face can trigger information transfer, or signaling, across the plasma membrane to "activate" cellular functions at the other face. Figure 1 illustrates this bidirectional signaling using ␣IIb␤3 as an example.Basic research conducted in the past 3 decades on many facets of ␣IIb␤3 structure and function has led to remarkable breakthroughs culminating in the development of a chimeric anti-␣IIb␤3 monoclonal antibody and small-molecule receptor antagonists now used parenterally to limit the formation of occlusive platelet thrombi in acute cardiovascular indications. 5,6 On the other hand, clinical trials of oral ␣IIb␤3 antagonists have been disappointing and suggest that long-term extracellular blockade of ligand binding ...

IntroductionPlatelet endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kD member of the immunoglobulin (Ig) superfamily that is expressed on the surface of circulating platelets, monocytes, neutrophils, and selected T cell subsets. It is also a major constituent of the endothelial cell intercellular junction (1-3), where up to 10 6 PECAM-1 molecules (4) are concentrated. With a few minor exceptions, PECAM-1 is not present on fibroblasts, epithelium, muscle, or other nonvascular cells. Since its cloning nearly 10 yr ago (5, 6), much has been learned about the structure of this cell adhesion receptor and its function in vascular cells. The purpose of this brief Perspective is to review progress in the field of PECAM-1 biology, and to bring the reader up to date on current concepts about ( a ) the function of PECAM-1 in the different vascular cells in which it is expressed; ( b ) the molecular mechanisms by which PECAM-1 mediates cell-cell interactions; and ( c ) its role in bidirectional transmembrane signal transduction. In keeping with the intent of this series to discuss issues of cell adhesion in the context of human biology and pathophysiology, the potential clinical relevance of PECAM-1-mediated cellular interactions to thrombotic, inflammatory, and immunological diseases will be underscored at relevant points throughout the review.

Abstract. PECAM-1 is a 130-120-kD integral membrane glycoprotein found on the surface of platelets, at endothelial intercellular junctions in culture, and on cells of myeloid lineage. Previous studies have shown that it is a member of the immunoglobulin gene superfamily and that antibodies against the bovine form of this protein (endoCAM) can inhibit endothelial cell-cell interactions . These data suggest that PECAM-1 may function as a vascular cell adhesion molecule . The function of this molecule has been further evaluated by transfecting cells with a full-length PECAM-1 cDNA . Transfected COS-7, mouse 3T3 and L cells expressed a 130-12041) glycoprotein on their cell surface that reacted with anti-PECAM-1 poly-