Ma Yan-Qing, Qin Jun, Wu Chuanyue, Plow Edward F
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195, USA.
J Cell Biol. 2008 May 5;181(3):439-46. doi: 10.1083/jcb.200710196.
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(3) this is an NPLY(747) motif and the membrane-proximal region. Here, we show that the C-terminal region of integrin beta(3) CT, composed of a conserved TS(752)T region and NITY(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(IIb)beta(3) activation. Furthermore, siRNA knockdown of endogenous kindlin-2 impairs talin-induced alpha(IIb)beta(3) activation in transfected CHO cells and blunts alpha(v)beta(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.
整合素激活对于动态连接细胞外环境与细胞骨架/信号网络至关重要。激活过程由整合素的短细胞质尾巴（CTs）控制。人们普遍认为，踝蛋白头部结构域（talin-H）可通过与整合素β亚基CT中的两个位点结合来介导整合素激活；在整合素β3中，这两个位点是NPLY(747)基序和膜近端区域。在此，我们表明整合素β3 CT的C末端区域，由保守的TS(752)T区域和NITY(759)基序组成，通过与一种胞质结合伴侣——黏着斑蛋白2（一种广泛分布的PTB结构域蛋白）结合来支持整合素激活。黏着斑蛋白2与talin-H共转染会导致整合素α(IIb)β3激活的协同增强。此外，对内源性黏着斑蛋白2进行小干扰RNA敲低会损害转染的CHO细胞中踝蛋白诱导的α(IIb)β3激活，并减弱α(v)β3介导的内皮细胞黏附和迁移。因此，我们的结果确定黏着斑蛋白2是整合素激活的一种新型调节因子；它作为一种共激活因子发挥作用。
