Collaborative Research Program for Cell Adhesion Molecules, Shanghai University School of Life Sciences, Shanghai 200444, China.
Blood Research Institute, Blood Center of Wisconsin, Wisconsin, WI 53226, USA.
J Cell Sci. 2017 Nov 1;130(21):3764-3775. doi: 10.1242/jcs.205641. Epub 2017 Sep 27.
Kindlins play an important role in supporting integrin activation by cooperating with talin; however, the mechanistic details remain unclear. Here, we show that kindlins interacted directly with paxillin and that this interaction could support integrin αIIbβ3 activation. An exposed loop in the N-terminal F subdomain of kindlins was involved in mediating the interaction. Disruption of kindlin binding to paxillin by structure-based mutations significantly impaired the function of kindlins in supporting integrin αIIbβ3 activation. Both kindlin and talin were required for paxillin to enhance integrin activation. Interestingly, a direct interaction between paxillin and the talin head domain was also detectable. Mechanistically, paxillin, together with kindlin, was able to promote the binding of the talin head domain to integrin, suggesting that paxillin complexes with kindlin and talin to strengthen integrin activation. Specifically, we observed that crosstalk between kindlin-3 and the paxillin family in mouse platelets was involved in supporting integrin αIIbβ3 activation and platelet thrombus formation. Taken together, our findings uncover a novel mechanism by which kindlin supports integrin αIIbβ3 activation, which might be beneficial for developing safer anti-thrombotic therapies.
Kindlins 在与 talin 合作支持整合素激活方面发挥着重要作用；然而，其机制细节仍不清楚。在这里，我们表明 kindlins 与 paxillin 直接相互作用，并且这种相互作用可以支持整合素 αIIbβ3 的激活。Kindlins 的 N 端 F 亚结构域中的一个暴露环参与介导相互作用。基于结构的突变破坏了 kindlins 与 paxillin 的结合，这显著削弱了 kindlins 在支持整合素 αIIbβ3 激活中的功能。kindlin 和 talin 都需要 paxillin 来增强整合素的激活。有趣的是，还可以检测到 paxillin 与 talin 头部结构域之间的直接相互作用。从机制上讲，paxillin 与 kindlin 一起能够促进 talin 头部结构域与整合素的结合，这表明 paxillin 与 kindlin 和 talin 形成复合物以增强整合素的激活。具体而言，我们观察到小鼠血小板中 kindlin-3 与 paxillin 家族之间的串扰参与了支持整合素 αIIbβ3 激活和血小板血栓形成。总之，我们的发现揭示了 kindlin 支持整合素 αIIbβ3 激活的新机制，这可能有益于开发更安全的抗血栓治疗方法。
