title: Regulation of the Pro-apoptotic scaffolding protein POSH by Akt.
abstract: 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.
authors.affiliation: Department of Pathology, the University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
authors.forename: Traci R
authors.initials: TR
authors.lastname: Lyons
authors.forename: Jackie
authors.initials: J
authors.lastname: Thorburn
authors.forename: Philip W
authors.initials: PW
authors.lastname: Ryan
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
authors.forename: Steven M
authors.initials: SM
authors.lastname: Anderson
authors.forename: C Kenneth
authors.initials: CK
authors.lastname: Kassenbrock
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D006801:Humans; D007668:Kidney; D008969:Molecular Sequence Data; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011993:Recombinant Fusion Proteins; C498193:SH3RF1 protein, human; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt