Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / genetics
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Cell Division / drug effects
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Cell Line
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Cell Survival / drug effects
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Enzyme Inhibitors / pharmacology
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Interleukin-3 / pharmacology
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Mitochondria / drug effects
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Mitochondria / enzymology
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Models, Biological
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Phosphorylation
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Point Mutation
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Protein Processing, Post-Translational / drug effects
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Rats
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Recombinant Fusion Proteins / metabolism
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Ribosomal Protein S6 Kinases / antagonists & inhibitors
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Ribosomal Protein S6 Kinases / physiology*
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Sirolimus / pharmacology
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bcl-Associated Death Protein
Substances
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Bad protein, rat
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Carrier Proteins
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Enzyme Inhibitors
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Interleukin-3
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Recombinant Fusion Proteins
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bcl-Associated Death Protein
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Insulin-Like Growth Factor I
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Ribosomal Protein S6 Kinases
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Sirolimus