Abstract
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 β's CT; in integrin β3 this is an NPLY747 motif and the membrane-proximal region. Here, we show that the C-terminal region of integrin β3 CT, composed of a conserved TS752T region and NITY759 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 αIIbβ3 activation. Furthermore, siRNA knockdown of endogenous kindlin-2 impairs talin-induced αIIbβ3 activation in transfected CHO cells and blunts αvβ3-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.
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