MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.
MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.
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DOI：
10.1038/ncomms9357
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发表时间：
2015-10-05
影响因子：
16.6
通讯作者：
Guan KL
中科院分区：
文献类型：
--
作者：
Meng Z;Moroishi T;Mottier-Pavie V;Plouffe SW;Hansen CG;Hong AW;Park HW;Mo JS;Lu W;Lu S;Flores F;Yu FX;Halder G;Guan KL
Hippo通路在组织平衡中起着核心作用，其失调有助于肿瘤的发生。Hippo通路的核心成分包括MST1/2和LATS1/2的激酶级联以及转录共激活因子YAP/TAZ。在刺激下，LATS1/2磷酸化并抑制Hippo通路的主要效应因子YAP/TAZ。越来越多的证据表明，MST1/2不是调控YAP/TAZ所必需的。我们发现，缺失LATS1/2而非MST1/2会消除YAP/TAZ磷酸化。我们已经鉴定出MAP4K家族成员——果蝇Happyhour同源物MAP4K1/2/3和Misshapen同源物map4k4 /6/7——是直接激活lats1 /2的激酶。MAP4Ks和MST1/2的联合缺失，但两者都不单独缺失，可以抑制LATS1/2和YAP/TAZ的磷酸化，以响应广泛的信号。我们的研究结果表明，MAP4Ks在调节LATS1/2和YAP/TAZ中与MST1/2平行，部分冗余，并确定MAP4Ks是扩展的Hippo通路的组成部分。已经报道了多种信号激活或抑制Hippo激酶级联反应。在这里，孟等人表明，丝裂原活化蛋白激酶激酶激酶激酶（MAP4K）家族成员在响应上游信号调节LATS时与MST1/2平行并部分冗余。
The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members—Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7—as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway. A variety of signals have been reported to either activate or inhibit the Hippo kinase cascade. Here, Meng et al. show that mitogen activated protein kinase kinase kinase kinase (MAP4K) family members function in parallel to and are partially redundant with MST1/2 in regulating LATS in response to upstream signals.