FRAP-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation

M. E. Hartman, M. Villela-Bach, J. Chen, G. G. Freund

Research output: Contribution to journalArticle

Abstract

We have previously shown that interferon-α (IFNα)-dependent tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired by serine phosphorylation of IRS-1 due to the reduced ability of serine phosphorylated IRS-1 to serve as a substrate for Janus kinase I (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFNα signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70s6k) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1511-772). Importantly, only FRAP-dependent IRS-1511-772 serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFNα-dependent tyrosine phosphorylation by twofold while reducing constitutive IRS-1 serine phosphorylation within S/T-P motifs by 80%. Taken together, these data indicate that FRAP, but not p70s6k, is a likely physiologic IRS-1 serine kinase that negatively regulates JAK1-dependent IRS-1 tyrosine phosphorylation and suggests that FRAP may modulate IRS-dependent cytokine signaling.

Original languageEnglish (US)
Article number94214
Pages (from-to)776-781
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume280
Issue number3
DOIs
StatePublished - 2001

Keywords

  • Cytokine resistance
  • FRAP
  • IFNα
  • IRS-1
  • JAK1
  • RAFT1
  • Rapamycin
  • Serine phosphorylation
  • mTOR
  • p70

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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