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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinogenesis / genetics
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Drosophila
  • Drosophila Proteins
  • Fluorescent Antibody Technique
  • Germinal Center Kinases
  • HEK293 Cells
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Homeostasis / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • Germinal Center Kinases
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YY1AP1 protein, human
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • TAFAZZIN protein, human
  • LATS1 protein, human
  • STK3 protein, human
  • LATS2 protein, human
  • MAP4K4 protein, human
  • hematopoietic progenitor kinase 1
  • Hippo protein, human
  • MAP4K3 protein, human
  • MINK1 protein, human
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila