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

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