Mst2 and lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP)
Mst2 and lats kinases regulate apoptotic function of Yes kinase-associated protein (YAP)
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DOI：
10.1074/jbc.m804380200
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发表时间：
2008-10-10
影响因子：
4.8
通讯作者：
Sudol, Marius
中科院分区：
文献类型：
--
作者：
Oka, Tsutomu;Mazack, Virginia;Sudol, Marius
果蝇中的Hippo通路控制器官的大小和形状。在果蝇中，该途径的激活传递生长抑制信号并促进上皮细胞的凋亡。我们在人类上皮细胞系中“重建”了Hippo通路，并表明，与苍蝇相反，该通路的激活导致抗凋亡信号。我们已经表明，在人胚肾（HEK）293细胞中，转录共激活因子YAP（Yes激酶相关蛋白）和Lats激酶之间的复合物形成需要YAP的完整WW结构域，以及Lats激酶中的完整Pro-Pro-AA-Tyr（其中AA是任何氨基酸）基序。这些激酶与上游Mst 2激酶合作以在Ser 127处磷酸化YAP。YAP 2在HEK 293细胞中的过表达促进了细胞凋亡，而Mst 2/Lats 1诱导的雅普磷酸化部分地拯救了细胞免于凋亡性死亡。YAP 2的凋亡信号通过稳定p73介导，p73与YAP 2形成复合物。我们研究的Hippo通路的所有组分都位于细胞质中，除了雅普，它也位于细胞核中。YAP 2在细胞核中的定位由Lats 1激酶负控制。我们在胚胎肾细胞中的海马通路的凋亡“读出”代表了一个有用的实验系统，用于鉴定推定的上游受体、膜蛋白或细胞外因子，其启动整个信号级联并最终控制器官的大小。
The Hippo pathway in Drosophila controls the size and shape of organs. In the fly, activation of this pathway conveys growth-inhibitory signals and promotes apoptosis in epithelial cells. We "reconstituted" the Hippo pathway in a human epithelial cell line and showed that, in contrast to flies, the activation of this pathway results in anti-apoptotic signals. We have shown that in human embryonic kidney (HEK) 293 cells, the complex formation between transcriptional co-activators YAPs (Yes kinase-associated proteins) and Lats kinases requires the intact WW domains of YAPs, as well as intact Pro-Pro-AA-Tyr (where AA is any amino acid) motifs in Lats kinases. These kinases cooperate with the upstream Mst2 kinase to phosphorylate YAPs at Ser127. Overexpression of YAP2 in HEK293 cells promoted apoptosis, whereas the Mst2/Lats1-induced phosphorylation of YAP partially rescued the cells from apoptotic death. Apoptotic signaling of YAP2 was mediated via stabilization of p73, which formed a complex with YAP2. All components of the Hippo pathway that we studied were localized in the cytoplasm, with the exception of YAP, which also localized in the nucleus. The localization of YAP2 in the nucleus was negatively controlled by the Lats1 kinase. Our apoptotic "readout" of the Hippo pathway in embryonic kidney cells represents a useful experimental system for the identification of the putative upstream receptor, membrane protein, or extracellular factor that initiates an entire signaling cascade and ultimately controls the size of organs.