Department of Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
Department of Physics, University of North Carolina, Chapel Hill, NC.
J Cell Biol. 2019 Jun 3;218(6):1958-1971. doi: 10.1083/jcb.201807152. Epub 2019 Apr 2.
Too little or too much force can trigger cell death, yet factors that ensure the survival of cells remain largely unknown. Here, we demonstrate that E-cadherin responds to force by recruiting and activating p21-activated protein kinase 2 (PAK2) to allow cells to stiffen, metabolize, and survive. Interestingly, PAK2 activation and its control of the apoptotic response are specific for the amplitude of force applied. Specifically, under low amplitudes of physiological force, PAK2 is protected from proteolysis, thereby ensuring cell survival. In contrast, under higher amplitudes of physiological force, PAK2 is left unprotected and stimulates apoptosis, an effect that is prevented by cleavage-resistant forms of the protein. Finally, we demonstrate that PAK2 protection is conferred by direct binding of AMPK. Thus, PAK2 mediates the survival of cells under force. These findings reveal an unexpected paradigm for how mechanotransduction, metabolism, and cell survival are linked.
力太弱或太强都可能触发细胞死亡，但能确保细胞存活的因素在很大程度上仍是未知的。在这里，我们证明 E-钙黏蛋白通过招募并激活丝裂原活化蛋白激酶 2（PAK2）对力作出响应，从而使细胞能够变硬、代谢并存活。有趣的是，PAK2 的激活及其对细胞凋亡反应的控制是针对施加力的幅度特异性的。具体而言，在生理力的低幅度下，PAK2 受到保护而免于蛋白水解，从而确保细胞存活。相比之下，在更高幅度的生理力下，PAK2 不受保护并刺激细胞凋亡，而该蛋白的不易被切割形式可防止这种效应。最后，我们证明 PAK2 的保护是由 AMPK 的直接结合赋予的。因此，PAK2 介导了细胞在力的作用下的存活。这些发现揭示了机械转导、代谢和细胞存活如何相互关联的一个出人意料的范例。
