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

Breast Cancer Res Treat. 2005 Jun;91(3):259-69. doi: 10.1007/s10549-005-0669-0.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Oligonucleotides, Antisense
  • Phosphoproteins
  • Protein Synthesis Inhibitors
  • Tyrosine
  • Serine
  • Insulin-Like Growth Factor I
  • Anisomycin
  • Protein Kinases
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • PRKCD protein, human
  • Protein Kinase C
  • Protein Kinase C-delta
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases