Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor.
Angiomotin family proteins are novel activators of the LATS2 kinase tumor suppressor.
复制标题
DOI：
10.1091/mbc.e11-04-0300
复制
发表时间：
2011-10
影响因子：
3.3
通讯作者：
McCollum D
中科院分区：
文献类型：
--
作者：
Paramasivam M;Sarkeshik A;Yates JR 3rd;Fernandes MJ;McCollum D
Hippo通路激酶LATS2促进接触抑制生长。LATS2如何响应细胞密度的变化而被激活尚不清楚。我们发现紧密连接蛋白AMOTL2是一种新的LATS2激活剂，这就提出了紧密连接组装促进LATS2依赖性细胞增殖抑制的可能性。LATS2激酶作为Hippo通路的一部分，通过磷酸化和抑制转录辅激活因子YAP，促进接触抑制生长和肿瘤抑制。LATS2被MST2激酶激活。LATS2如何被MST2激活以响应细胞密度的变化尚不清楚。在这里，我们发现血管运动素家族紧密连接蛋白AMOTL2是一种新的LATS2激活剂。像AMOTL2一样，其他血管平滑素家族蛋白AMOT和AMOTL1也通过一个新的结合和激活LATS2的保守结构域激活LATS2。AMOTL2结合MST2、LATS2和YAP，提示AMOTL2可能作为支架蛋白。我们发现LATS2、AMOTL2和YAP都定位于紧密连接，这提高了Hippo通路组分在紧密连接处聚集的可能性，可能在细胞密度增加的情况下触发LATS2激活和生长抑制。
The Hippo pathway kinase LATS2 promotes contact inhibition of growth. How LATS2 is activated in response to changes in cell density is unknown. It is found that tight junction protein AMOTL2 is a novel activator of LATS2, raising the possibility that tight junction assembly promotes LATS2-dependent inhibition of cell proliferation. LATS2 kinase functions as part of the Hippo pathway to promote contact inhibition of growth and tumor suppression by phosphorylating and inhibiting the transcriptional coactivator YAP. LATS2 is activated by the MST2 kinase. How LATS2 is activated by MST2 in response to changes in cell density is unknown. Here we identify the angiomotin-family tight junction protein AMOTL2 as a novel activator of LATS2. Like AMOTL2, the other angiomotin-family proteins AMOT and AMOTL1 also activate LATS2 through a novel conserved domain that binds and activates LATS2. AMOTL2 binds MST2, LATS2, and YAP, suggesting that AMOTL2 might serve as a scaffold protein. We show that LATS2, AMOTL2, and YAP all localize to tight junctions, raising the possibility that clustering of Hippo pathway components at tight junctions might function to trigger LATS2 activation and growth inhibition in response to increased cell density.