Abstract
IRS-1 (Insulin Receptor Substrate-1) is an adaptor protein important for insulin and IGF-I receptor (Insulin-like Growth Factor-IR) transduction to downstream targets. One mechanism recently identified to downregulate IGF-I or insulin receptor signaling in diabetic models is IRS-1 Ser(312) phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser(312) regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS(312) is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS(312). We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCdelta (Protein Kinase C-delta) to induce IRS-1 Ser(312) phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser(312) phosphorylation in response to stress or IGF-I treatment. PKCdelta binds to mTOR and its activity is also important for stress or IGF-I mediated Ser(312) phosphorylation. Thus, mTOR and PKCdelta convey diverse signals to regulate IRS-1 function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Anisomycin / pharmacology
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Enzyme Activation
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Female
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Humans
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / pharmacology*
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Oligonucleotides, Antisense / pharmacology
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Kinase C / metabolism*
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Protein Kinase C-delta
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Protein Kinases / chemistry
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Synthesis Inhibitors / pharmacology
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Serine / chemistry
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Signal Transduction
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TOR Serine-Threonine Kinases
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Tumor Cells, Cultured
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Tyrosine / metabolism
Substances
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IRS1 protein, human
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Insulin Receptor Substrate Proteins
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Oligonucleotides, Antisense
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Phosphoproteins
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Protein Synthesis Inhibitors
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Tyrosine
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Serine
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Insulin-Like Growth Factor I
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Anisomycin
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Protein Kinases
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MTOR protein, human
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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PRKCD protein, human
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Protein Kinase C
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Protein Kinase C-delta
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases