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MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway

机译:MAP4K家族激酶与MST1 / 2平行起作用以激活Hippo途径中的LATS1 / 2

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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.
机译:Hippo通路在组织稳态中起着核心作用,其失调有助于肿瘤的发生。 Hippo途径的核心成分包括MST1 / 2和LATS1 / 2的激酶级联反应以及转录共激活因子YAP / TAZ。响应刺激,LATS1 / 2磷酸化并抑制HAP途径的主要效应物YAP / TAZ。越来越多的证据表明,YST / TAZ的调节不需要MST1 / 2。在这里,我们显示删除LATS1 / 2而不删除MST1 / 2消除了YAP / TAZ磷酸化。我们已经确定了MAP4K家族成员-果蝇Happyhour同源物MAP4K1 / 2/3和Misshapen同源物MAP4K4 / 6 / 7-是直接的LATS1 / 2激活激酶。 MAP4Ks和MST1 / 2的组合缺失,但两者都不是,可抑制LATS1 / 2和YAP / TAZ的磷酸化,以响应多种信号。我们的研究结果表明,MAP4Ks在调控LATS1 / 2和YAP / TAZ方面与MST1 / 2平行发挥作用,并在MST1 / 2上有部分冗余,并将MAP4Ks确立为扩大的Hippo途径的组成部分。

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