Department of Microbial and Physiological Systems and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Mol Biol Cell. 2011 Oct;22(19):3725-33. doi: 10.1091/mbc.E11-04-0300. Epub 2011 Aug 10.
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.
LATS2 激酶作为 Hippo 通路的一部分发挥作用，通过磷酸化并抑制转录共激活因子 YAP 来促进生长的接触抑制和肿瘤抑制。LATS2 被 MST2 激酶激活。MST2 激酶如何响应细胞密度的变化激活 LATS2 尚不清楚。在这里，我们鉴定出血管生成素家族紧密连接蛋白 AMOTL2 是 LATS2 的一种新型激活剂。与 AMOTL2 一样，其他血管生成素家族蛋白 AMOT 和 AMOTL1 也通过结合并激活 LATS2 的新型保守结构域激活 LATS2。AMOTL2 与 MST2、LATS2 和 YAP 结合，表明 AMOTL2 可能作为支架蛋白发挥作用。我们表明，LATS2、AMOTL2 和 YAP 都定位于紧密连接，这增加了 Hippo 通路成分在紧密连接处聚集可能触发 LATS2 激活和生长抑制以响应细胞密度增加的可能性。
