Identification of Happyhour/MAP4K as Alternative Hpo/Mst-like Kinases in the Hippo Kinase Cascade

Yonggang Zheng, Wei Wang, Bo Liu, Hua Deng, Eliza Uster, Duojia Pan

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

In Drosophila and mammals, the canonical Hippo kinase cascade is mediated by Hpo/Mst acting through the intermediary kinase Wts/Lats to phosphorylate the transcriptional coactivator Yki/YAP/TAZ. Despite recent reports linking Yki/YAP/TAZ activity to the actin cytoskeleton, the underlying mechanisms are poorly understood and/or controversial. Using Drosophila imaginal discs as an in vivo model, we show that Wts, but not Hpo, is genetically indispensable for cytoskeleton-mediated subcellular localization of Yki. Through a systematic screen, we identify the Ste-20 kinase Happyhour (Hppy) and its mammalian counterpart MAP4K1/2/3/5 as an alternative kinase that phosphorylates the hydrophobic motif of Wts/Lats in a similar manner as Hpo/Mst. Consistent with their redundant function as activating kinases of Wts/Lats, combined loss of Hpo/Mst and Hppy/MAP4K abolishes cytoskeleton-mediated regulation of Yki/YAP subcellular localization, as well as YAP cytoplasmic translocation induced by contact inhibition. These Hpo/Mst-like kinases provide an expanded view of the Hippo kinase cascade in development and physiology. Although the Hippo pathway was named after the protein kinase Hpo, increasing evidence also suggests Hpo-independent activation of downstream signaling. Zheng et al. identify Happyhour and its mammalian counterpart as alternative Hpo-like kinases. Happyhour and Hpo function redundantly in Hippo pathway activation in response to cytoskeletal disruption or contact inhibition.

Original languageEnglish (US)
Pages (from-to)642-655
Number of pages14
JournalDevelopmental Cell
Volume34
Issue number6
DOIs
StatePublished - Sep 28 2015

ASJC Scopus subject areas

  • Developmental Biology

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