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

Zhipeng Meng, Toshiro Moroishi, Violaine Mottier-Pavie, Steven W. Plouffe, Carsten G. Hansen, Audrey W. Hong, Hyun Woo Park, Jung Soon Mo, Wenqi Lu, Shicong Lu, Fabian Flores, Fa Xing Yu, Georg Halder, Kun Liang Guan

Research output: Contribution to journalArticlepeer-review

299 Citations (Scopus)


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.

Original languageEnglish
Article number8357
JournalNature communications
Publication statusPublished - 2015 Oct 5

Bibliographical note

Funding 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).

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


Dive into the research topics of 'MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway'. Together they form a unique fingerprint.

Cite this