ADHESION IS REQUIRED for cell growth, differentiation, survival, and function. Nowhere is this more evident than in the response to tissue injury, where vascular damage triggers reparative processes, such as hemostasis, inflammation, and wound healing. These processes depend on a coordinated series of cell adhesion and migration events by platelets, leukocytes, and vascular cells for their successful execution. 1 Cell adhesion is mediated by a structurally diverse group of plasma membrane receptors, each exhibiting specialized ligand-binding properties that are needed for specific tasks in the injury response. For example, when blood flows through a damaged blood vessel, leukocytes slow down and roll on the endothelial surface as a consequence of the interaction of appropriate sialyl Lewis X-rich membrane glycoproteins on the leukocytes with selectins on the endothelial cells. 2, 3 Platelets also roll under conditions of high shear on perturbed endothelium4 as well as on denuded vascular surfaces, in the latter case through interactions of the platelet glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) in the subendothelial matrix. 5 Once the rolling process has slowed down these blood cells, they come to an abrupt stop at the right place through regulated interactions between integrin adhesion receptors and either counter-receptors on endothelial cells or adhesive proteins in the matrix. 2, 5 Integrins also mediate responses necessary for eventual completion of the injury response, including leukocyte transmigration and platelet aggregation. 2, 6 Although adhesion receptors rightfully deserve this moniker, any implication that they are simply cellular velcro is incorrect. Most, if not all, adhesion receptors engage in a dialogue with the extracellular and intracellular milieus. Integrins are a case in point. Cells often regulate ligand binding to integrins through a process known as inside-out signaling or integrin activation. Furthermore, once integrins have become occupied and clustered by their ligands, they can transmit information into cells. These outside-in signals collaborate with signals originating from growth factor receptors and other plasma membrane receptors to regulate a host of anchorage-dependent cellular functions. One of the best studied cases of integrin signaling involves ɑIIbß3, an integrin of particular significance to hematologists because it is required for aggregation and adhesive spreading of platelets during hemostasis (Fig 1). The purpose of this review is to describe the platelet paradigm of integrin signaling and to emphasize the advances and gaps in our understanding of this process and place it into clinical perspective. We have tried to cite authoritative reviews whenever possible to provide interested readers with additional sources of primary references. Several excellent general reviews of integrins7-12 and platelet biochemistry13, 14 are available.

WHAT IS INTEGRIN SIGNALING? ɑIIbß3 consists of a two-chain ɑ subunit bound noncovalently to a single-chain ß subunit. Each subunit spans the platelet membrane once. The N-terminus and most of the remainder of each subunit are extracellular, and the membrane-spanning domain is connected to a short C-terminal cytoplasmic tail