p90(RSK) blocks bad-mediated cell death via a protein kinase C-dependent pathway.
Although activation of protein kinase C (PKC) is known to promote cell survival and protect against cell death, the PKC targets and pathways that serve this function have remained elusive. Here we demonstrate that two potent activators of PKC, 12-O-tetradecanoylphorbol-13-acetate and bryostatin, both stimulate phosphorylation of Bad at Ser(112), a site known to regulate apoptotic cell death by interleukin-3. PKC inhibitors but not PI 3-kinase/Akt inhibitors block 12-O-tetradecanoylphorbol-13-acetate-stimulated Bad phosphorylation. PKC isoforms tested in vitro were unable to phosphorylate Bad at Ser(112), suggesting that PKC acts indirectly to activate a downstream Bad kinase. p90(RSK) and family members RSK-2 and RSK-3 are activated by phorbol ester and phosphorylate Bad at Ser(112) both in vitro and in vivo. p90(RSK) stimulates binding of Bad to 14-3-3 and blocks Bad-mediated cell death in a Ser(112)-dependent manner. These findings suggest that p90(RSK) can function in a PKC-dependent pathway to promote cell survival via phosphorylation and inactivation of Bad-mediated cell death.
Tan
Y
Y
Cell Signaling Laboratory, New England Biolabs, Beverly, Massachusetts 01915, USA. tan@neb.com
Ruan
H
H
Demeter
M R
MR
Comb
M J
MJ
D000818:Animals; D017209:Apoptosis; D054713:Bryostatins; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D054713:Bryostatins; D002352:Carrier Proteins; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D051025:bcl-Associated Death Protein; C046785:bryostatin 1; D012694:Serine; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate