Mob as tumor suppressor is activated by Hippo kinase for growth inhibition in Drosophila

EMBO J. 2007 Apr 4;26(7):1772-81. doi: 10.1038/sj.emboj.7601630. Epub 2007 Mar 8.

Abstract

Tissue growth and organ size are determined by coordinated cell proliferation and apoptosis in development. Recent studies have demonstrated that Hippo (Hpo) signaling plays a crucial role in coordinating these processes by restricting cell proliferation and promoting apoptosis. Here we provide evidence that the Mob as tumor suppressor protein, Mats, functions as a key component of the Hpo signaling pathway. We found that Mats associates with Hpo in a protein complex and is a target of the Hpo serine/threonine protein kinase. Mats phosphorylation by Hpo increases its affinity with Warts (Wts)/large tumor suppressor (Lats) serine/threonine protein kinase and ability to upregulate Wts catalytic activity to target downstream molecules such as Yorkie (Yki). Consistently, our epistatic analysis suggests that mats acts downstream of hpo. Coexpression analysis indicated that Mats can indeed potentiate Hpo-mediated growth inhibition in vivo. Our results support a model in which Mats is activated by Hpo through phosphorylation for growth inhibition, and this regulatory mechanism is conserved from flies to mammals.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Survival
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / growth & development*
  • Enzyme Activation
  • Epistasis, Genetic
  • Eye / cytology
  • Eye / ultrastructure
  • Intracellular Signaling Peptides and Proteins
  • Larva / cytology
  • Models, Biological
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Binding
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism*
  • Substrate Specificity
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation / genetics

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mats protein, Drosophila
  • Phosphoproteins
  • Tumor Suppressor Proteins
  • sav protein, Drosophila
  • Protein Kinases
  • wts protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila