Kindlin-2 (Mig-2): a co-activator of [[beta].sub.3] integrins

Integrin activation is essential for dynamically linking the extracellular environment and cytoskeletal/signaling networks. Activation is controlled by integrins' short cytoplasmic tails (CTs). It is widely accepted that the head domain of talin (talin-H) can mediate integrin activation by binding to two sites in integrin [beta]'s CT; in integrin [[beta].sub.3] this is an NPL[Y.sup.747] motif and the membrane-proximal region. Here, we show that the C-terminal region of integrin [[beta].sub.3] CT, composed of a conserved T[S.sup.752]T region and NIT[Y.sup.759] motif, supports integrin activation by binding to a cytosolic binding partner, kindlin-2, a widely distributed PTB domain protein. Co-transfection of kindlin-2 with talin-H results in a synergistic enhancement of integrin [[alpha].sub.IIb][[beta].sub.3] activation. Furthermore, siRNA knockdown of endogenous kindlin-2 impairs talin-induced [[alpha].sub.IIb][[beta].sub.3] activation in transfected CHO cells and blunts [[alpha].sub.v][[beta].sub.3]-mediated adhesion and migration of endothelial cells. Our results thus identify kindlin-2 as a novel regulator of integrin activation; it functions as a coactivator.