Adaptor protein cerebral cavernous malformation 3 (CCM3) mediates phosphorylation of the cytoskeletal proteins ezrin/radixin/moesin by mammalian Ste20-4 to protect cells from oxidative stress

J Biol Chem. 2012 Mar 30;287(14):11556-65. doi: 10.1074/jbc.M111.320259. Epub 2012 Jan 30.

Abstract

While studying the functions of CCM3/PDCD10, a gene encoding an adaptor protein whose mutation results in vascular malformations, we have found that it is involved in a novel response to oxidative stress that results in phosphorylation and activation of the ezrin/radixin/moesin (ERM) family of proteins. This phosphorylation protects cells from accidental cell death induced by oxidative stress. We also present evidence that ERM phosphorylation is performed by the GCKIII kinase Mst4, which is activated and relocated to the cell periphery after oxidative stress. The cellular levels of Mst4 and its activation after oxidative stress depend on the presence of CCM3, as absence of the latter impairs the phosphorylation of ERM proteins and enhances death of cells exposed to reactive oxygen species. These findings shed new light on the response of cells to oxidative stress and identify an important pathophysiological situation in which ERM proteins and their phosphorylation play a significant role.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Death
  • Cell Line
  • Cytoskeletal Proteins / metabolism*
  • Humans
  • Membrane Proteins / metabolism*
  • Microfilament Proteins / metabolism
  • Oxidative Stress*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Transport
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Cytoskeletal Proteins
  • Membrane Proteins
  • Microfilament Proteins
  • PDCD10 protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • ezrin
  • moesin
  • radixin
  • STK26 protein, human
  • Protein-Serine-Threonine Kinases