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.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health (CA132809, EY022611, DEO15964, CA23100 and CA196878, K.-L.G.). T.M. is supported by the Japan Society for the Promotion of Science (JSPS) Postdoctoral Fellowships for Research Abroad and by a grant from the Yasuda Medical Foundation. C.G.H. is supported by a Postdoctoral Fellowship from the Danish Council for Independent Research | Nature Sciences. S.W.P. and A.W.H. were supported in part by a University of California, San Diego (UCSD) Graduate Training Programme in Cellular and Molecular Pharmacology training grant (T32 GM007752).
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)