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.
Lyons
Traci R
TR
Department of Pathology, the University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Thorburn
Jackie
J
Ryan
Philip W
PW
Thorburn
Andrew
A
Anderson
Steven M
SM
Kassenbrock
C Kenneth
CK
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*
D011993:Recombinant Fusion Proteins; C498193:SH3RF1 protein, human; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt