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

Nat Commun. 2015 Oct 5:6:8357. doi: 10.1038/ncomms9357.

Zhipeng Meng ¹, Toshiro Moroishi ¹, Violaine Mottier-Pavie ², Steven W Plouffe ¹, Carsten G Hansen ¹, Audrey W Hong ¹, Hyun Woo Park ¹, Jung-Soon Mo ¹, Wenqi Lu ¹, Shicong Lu ¹, Fabian Flores ¹, Fa-Xing Yu ³, Georg Halder ², Kun-Liang Guan ¹

Affiliations

1 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
2 Vlaams Instituut voor Biotechnologie Center for the Biology of Disease and Katholieke Universiteit Leuven Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium.
3 Children's Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

PMID: 26437443 DOI: 10.1038/ncomms9357

Abstract

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.

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