p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD.
Cytokines often deliver simultaneous, yet distinct, cell growth and cell survival signals. The 70-kDa ribosomal protein S6 kinase (p70S6K) is known to regulate cell growth by inducing protein synthesis components. We purified membrane-based p70S6K as a kinase responsible for site-specific phosphorylation of BAD, which inactivates this proapoptotic molecule. Rapamycin inhibited mitochondrial-based p70S6K, which prevented phosphorylation of Ser-136 on BAD and blocked cell survival induced by insulin-like growth factor 1 (IGF-1). Moreover, IGF-1-induced phosphorylation of BAD Ser-136 was abolished in p70S6K-deficient cells. Thus, p70S6K is itself a dual pathway kinase, signaling cell survival as well as growth through differential substrates which include mitochondrial BAD and the ribosomal subunit S6, respectively.
Harada
H
H
Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Andersen
J S
JS
Mann
M
M
Terada
N
N
Korsmeyer
S J
SJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors; D007377:Interleukin-3 / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D011993:Recombinant Fusion Proteins; D051025:bcl-Associated Death Protein; D007334:Insulin-Like Growth Factor I; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus