Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway NJ 08854, USA.
Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway NJ 08854, USA
J Cell Sci. 2018 Mar 2;131(5):jcs214700. doi: 10.1242/jcs.214700.
Hippo signaling is regulated by biochemical and biomechanical cues that influence the cytoskeleton, but the mechanisms that mediate this have remained unclear. We show that all three mammalian Ajuba family proteins - AJUBA, LIMD1 and WTIP - exhibit tension-dependent localization to adherens junctions, and that both LATS family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization. This localization of Ajuba and LATS family proteins is also influenced by cell density, and by Rho activation. We establish that junctional localization of LATS kinases requires LIMD1, and that LIMD1 is also specifically required for the regulation of LATS kinases and YAP1 by Rho. Our results identify a biomechanical pathway that contributes to regulation of mammalian Hippo signaling, establish that this occurs through tension-dependent LIMD1-mediated recruitment and inhibition of LATS kinases in junctional complexes, and identify roles for this pathway in both Rho-mediated and density-dependent regulation of Hippo signaling.
Hippo 信号通路受到影响细胞骨架的生化和生物力学线索的调节，但介导这种调节的机制仍不清楚。我们发现三种哺乳动物 Ajuba 家族蛋白（AJUBA、LIMD1 和 WTIP）均表现出对黏着连接的张力依赖性定位，并且 LATS 家族蛋白 LATS1 和 LATS2 均表现出重叠的张力依赖性连接定位。Ajuba 和 LATS 家族蛋白的这种定位也受到细胞密度和 Rho 激活的影响。我们确定 LATS 激酶的连接定位需要 LIMD1，并且 LIMD1 也是 Rho 调节 LATS 激酶和 YAP1 所必需的。我们的结果确定了一种生物力学途径，该途径有助于调节哺乳动物 Hippo 信号通路，确定这是通过张力依赖性 LIMD1 介导的募集和抑制连接复合物中的 LATS 激酶来实现的，并确定该途径在 Rho 介导和密度依赖性 Hippo 信号通路调节中的作用。
