Identification of RUNX3 as a component of the MST/Hpo signaling pathway

J Cell Physiol. 2012 Feb;227(2):839-49. doi: 10.1002/jcp.22887.

Abstract

Recent genetic screens of fly mutants and molecular analysis have revealed that the Hippo (Hpo) pathway controls both cell proliferation and cell death. Deregulation of its human counterpart (the MST pathway) has been implicated in human cancers. However, how this pathway is linked with the known tumor suppressor network remains to be established. RUNX3 functions as a tumor suppressor of gastric cancer, lung cancer, bladder cancer, and colon cancer. Here, we show that RUNX3 is a principal and evolutionarily conserved component of the MST pathway. SAV1/WW45 facilitates the close association between MST2 and RUNX3. MST2, in turn, stimulates the SAV1-RUNX3 interaction. In addition, we show that siRNA-mediated RUNX3 knockdown abolishes MST/Hpo-mediated cell death. By establishing that RUNX3 is an endpoint effector of the MST pathway and that RUNX3 is capable of inducing cell death in cooperation with MST and SAV1, we define an evolutionarily conserved novel regulatory mechanism loop for tumor suppression in human cancers.

Publication types

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

MeSH terms

  • Animals
  • Biological Evolution
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Death
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / metabolism*
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Models, Molecular
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction / physiology*
  • Two-Hybrid System Techniques

Substances

  • Cell Cycle Proteins
  • Core Binding Factor Alpha 3 Subunit
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Runx3 protein, human
  • SAV1 protein, human
  • Protein Serine-Threonine Kinases
  • hpo protein, Drosophila
  • MAP Kinase Kinase Kinases
  • MAP3K10 protein, human