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Regulation of the Pro-apoptotic scaffolding protein POSH by Akt.

POSH (Plenty of SH3 domains) binds to activated Rac and promotes apoptosis by acting as a scaffold to assemble a signal transduction pathway leading from Rac to JNK activation. Overexpression of POSH induces apoptosis in a variety of cell types, but apoptosis can be prevented by co-expressing the pro-survival protein kinase Akt. We report here that POSH is a direct substrate for phosphorylation by Akt in vivo and in vitro, and we identify a major site of Akt phosphorylation as serine 304 of POSH, which lies within the Rac-binding domain. We further show that phosphorylation of POSH results in a decreased ability to bind activated Rac, as does phosphomimetic S304D and S304E mutation of POSH. S304D mutant POSH also shows a strongly reduced ability to induce apoptosis. These findings identify a novel mechanism by which Akt promotes cell survival.

Pubmed ID: 17535800

Authors

  • Lyons TR
  • Thorburn J
  • Ryan PW
  • Thorburn A
  • Anderson SM
  • Kassenbrock CK

Journal

The Journal of biological chemistry

Publication Data

July 27, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: CA111421
  • Agency: NIDDK NIH HHS, Id: DK063674

Mesh Terms

  • Apoptosis
  • Base Sequence
  • Cell Line
  • Cloning, Molecular
  • Humans
  • Kidney
  • Molecular Sequence Data
  • Proto-Oncogene Proteins c-akt
  • Recombinant Fusion Proteins
  • Restriction Mapping
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin-Protein Ligases