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Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway.

BACKGROUND: Hippo, a Drosophila serine/threonine kinase, promotes apoptosis and restricts cell growth and proliferation. Its mammalian homolog MST2 has been shown to play similar role and be regulated by Raf-1 via a kinase-independent mechanism and by RASSF family proteins through forming complex with MST2. However, regulation of MST2 by cell survival signal remains largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using immunoblotting, in vitro kinase and in vivo labeling assays, we show that IGF1 inhibits MST2 cleavage and activation induced by DNA damage through the phosphatidylinosotol 3-kinase (PI3K)/Akt pathway. Akt phosphorylates a highly conserved threonine-117 residue of MST2 in vitro and in vivo, which leads to inhibition of MST2 cleavage, nuclear translocation, autophosphorylation-Thr180 and kinase activity. As a result, MST2 proapoptotic and growth arrest function was significantly reduced. Further, inverse correlation between pMST2-T117/pAkt and pMST2-T180 was observed in human breast tumors. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate for the first time that extracellular cell survival signal IGF1 regulates MST2 and that Akt is a key upstream regulator of MST2.

Pubmed ID: 20231902

Authors

  • Kim D
  • Shu S
  • Coppola MD
  • Kaneko S
  • Yuan ZQ
  • Cheng JQ

Journal

PloS one

Publication Data

March 16, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA107078
  • Agency: NCI NIH HHS, Id: CA137041
  • Agency: NCI NIH HHS, Id: R01 CA137041
  • Agency: NCI NIH HHS, Id: R01 CA137041-03

Mesh Terms

  • Active Transport, Cell Nucleus
  • Animals
  • Breast Neoplasms
  • COS Cells
  • Caspase 3
  • Caspase 7
  • Cell Line
  • Cercopithecus aethiops
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Insulin-Like Growth Factor I
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction