The tumor suppressor RASSF1A prevents dephosphorylation of the mammalian STE20-like kinases MST1 and MST2

J Biol Chem. 2011 Feb 25;286(8):6253-61. doi: 10.1074/jbc.M110.178210. Epub 2011 Jan 3.

Abstract

The RASSF1A tumor suppressor protein interacts with the pro-apoptotic mammalian STE20-like kinases MST1 and MST2 and induces their autophosphorylation and activation, but the mechanism of how RASSF1A activates MST1/2 is unclear. Okadaic acid treatment and PP2A knockdown promoted MST1/2 phosphorylation. Data from dephosphorylation assays and reduced activation of MST1/2 seen after RASSF1A depletion suggest that dephosphorylation of MST1/2 on Thr-183 and Thr-180 by PP2A is prevented by RASSF1A, shifting the balance of MST1/2 to the activated autophosphorylated form. In addition to preventing dephosphorylation, RASSF1A also stabilized the MST2 protein. Through binding to MST1/2, RASSF1A supports maintenance of MST1/2 phosphorylation, promoting an active state of the MST kinases and favoring induction of apoptosis. This is one of the first examples of a tumor suppressor acting as an inhibitor of a specific dephosphorylation pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Humans
  • Okadaic Acid / pharmacology
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Enzyme Inhibitors
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • Okadaic Acid
  • STK3 protein, human
  • STK4 protein, human
  • Protein-Serine-Threonine Kinases
  • Protein Phosphatase 2