PKCdelta and mTOR interact to regulate stress and IGF-I induced IRS-1 Ser312 phosphorylation in breast cancer cells

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) phosphory...

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Bibliographic Details
Published in:Breast cancer research and treatment 2005-06, Vol.91 (3), p.259-269
Main Authors: Mingo-Sion, Amy M, Ferguson, Heather A, Koller, Erich, Reyland, Mary E, Van Den Berg, Carla L
Format: Article
Language:English
Subjects:
Anisomycin - pharmacology
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Enzyme Activation
Female
Humans
Insulin Receptor Substrate Proteins
Insulin-Like Growth Factor I - pharmacology
JNK Mitogen-Activated Protein Kinases - metabolism
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinase Kinases - metabolism
Oligonucleotides, Antisense - pharmacology
Phosphoproteins - metabolism
Phosphorylation
Protein Kinase C - metabolism
Protein Kinase C-delta
Protein Kinases - chemistry
Protein Kinases - genetics
Protein Kinases - metabolism
Protein Synthesis Inhibitors - pharmacology
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
Serine - chemistry
Signal Transduction
TOR Serine-Threonine Kinases
Tumor Cells, Cultured
Tyrosine - metabolism
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Summary: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.
ISSN:0167-6806