Apoptosis and Proliferation Control Laboratory, Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Mol Cell. 2010 Aug 27;39(4):521-34. doi: 10.1016/j.molcel.2010.08.002.
The Hippo (Hpo) pathway is a central determinant of tissue size in both Drosophila and higher organisms. The core of the pathway is a kinase cascade composed of an upstream kinase Hpo (MST1/2 in mammals) and a downstream kinase Warts (Wts, Lats1/2 in mammals), as well as several scaffold proteins, Sav, dRASSF, and Mats. Activation of the core kinase cassette results in phosphorylation and inactivation of the progrowth transcriptional coactivator Yki, leading to increased apoptosis and reduced tissue growth. The mechanisms that prevent inappropriate Hpo activation remain unclear, and in particular, the identity of the phosphatase that antagonizes Hpo is unknown. Using combined proteomic and RNAi screening approaches, we identify the dSTRIPAK PP2A complex as a major regulator of Hpo signaling. dSTRIPAK depletion leads to increased Hpo activatory phosphorylation and repression of Yki target genes in vivo, suggesting this phosphatase complex prevents Hpo activation during development.
Hippo（Hpo）途径是果蝇和高等生物组织大小的主要决定因素。该途径的核心是由上游激酶 Hpo（哺乳动物中的 MST1/2）和下游激酶 Warts（Wts，哺乳动物中的 Lats1/2）以及几个支架蛋白 Sav、dRASSF 和 Mats 组成的激酶级联反应。核心激酶盒的激活导致促生长转录共激活因子 Yki 的磷酸化和失活，从而导致细胞凋亡增加和组织生长减少。防止 Hpo 异常激活的机制尚不清楚，特别是拮抗 Hpo 的磷酸酶的身份尚不清楚。通过联合蛋白质组学和 RNAi 筛选方法，我们发现 dSTRIPAK PP2A 复合物是 Hpo 信号的主要调节剂。dSTRIPAK 耗竭导致体内 Hpo 激活磷酸化增加和 Yki 靶基因表达受抑制，表明该磷酸酶复合物在发育过程中防止 Hpo 激活。
