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

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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 Ser312 phosphorylation. To date, the importance of this residue in cancer is unknown. This paper identifies mechanisms leading to Ser312 regulation in MCF-7 breast cancer cells. Whereas IGF-I phosphorylation of IRS312 is PI (phosphatidylinositol) 3-kinase dependent, anisomycin stress treatment requires JNK activation to induce phosphorylation of IRS312. We show that both IGF-I and anisomycin stress treatment converge downstream onto mTOR (Mammalian Target of Rapamycin) and PKCδ (Protein Kinase C-delta) to induce IRS-1 Ser312 phosphorylation. mTOR associates with IRS-1 and is primarily required for Ser312 phosphorylation in response to stress or IGF-I treatment. PKCδ binds to mTOR and its activity is also important for stress or IGF-I mediated Ser312 phosphorylation. Thus, mTOR and PKCδ convey diverse signals to regulate IRS-1 function.