Tension-dependent regulation of mammalian Hippo signaling through LIMD1
Tension-dependent regulation of mammalian Hippo signaling through LIMD1
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DOI：
10.1242/jcs.214700
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发表时间：
2018-03-01
影响因子：
4
通讯作者：
Irvine, Kenneth D.
中科院分区：
文献类型：
--
作者：
Ibar, Consuelo;Kirichenko, Elmira;Irvine, Kenneth D.
Hippo信号受影响细胞骨架的生化和生物力学线索的调节，但介导这一点的机制仍不清楚。我们发现，所有三种哺乳动物筋骨草家族蛋白- AJUBA，LIMD 1和WTIP -表现出张力依赖性的本地化粘附连接，和两个LATS家族蛋白，LATS 1和LATS 2，表现出重叠的张力依赖性连接本地化。Ajuba和LATS家族蛋白的这种定位也受到细胞密度和Rho活化的影响。我们确定LATS激酶的连接定位需要LIMD 1，并且LIMD 1也是Rho调控LATS激酶和YAP 1所特别需要的。我们的研究结果确定了一个生物力学途径，有助于调节哺乳动物Hippo信号，建立这是通过张力依赖性LIMD 1介导的招聘和抑制LATS激酶在连接复合物，并确定这条途径在Rho介导和密度依赖性调节Hippo信号的作用。
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 tensiondependent localization to adherens junctions, and that both LATS family proteins, LATS1 and LATS2, exhibit an overlapping tensiondependent 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.