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

Biochem Biophys Res Commun. 2001 Jan 26;280(3):776-81. doi: 10.1006/bbrc.2000.4214.


We have previously shown that interferon-alpha (IFN alpha)-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 1 (JAK1). Here we report that FKBP12-rapamycin-associated protein (FRAP) is a physiologic IRS-1 kinase that blocks IFN alpha signaling by serine phosphorylating IRS-1. We found that both FRAP and insulin-activated p70 S6 kinase (p70(s6k)) serine phosphorylated IRS-1 between residues 511 and 772 (IRS-1(511-772)). Importantly, only FRAP-dependent IRS-1(511-772) serine phosphorylation inhibited by 50% subsequent JAK1-dependent tyrosine phosphorylation of IRS-1. Furthermore, treatment of U266 cells with the FRAP inhibitor rapamycin increased IFN alpha-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 p70(s6k), 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.

Publication types

  • 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

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins*
  • Cell Line
  • Humans
  • Immunophilins / chemistry*
  • Immunophilins / genetics
  • Immunophilins / metabolism*
  • Insulin Receptor Substrate Proteins
  • Interferon-alpha / pharmacology
  • Janus Kinase 1
  • Phosphoproteins / chemistry*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Phosphotransferases (Alcohol Group Acceptor)*
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Ribosomal Protein S6 Kinases / metabolism
  • Serine / chemistry
  • Signal Transduction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Tyrosine / chemistry


  • Carrier Proteins
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Interferon-alpha
  • Irs1 protein, rat
  • Phosphoproteins
  • Tyrosine
  • Serine
  • Phosphotransferases (Alcohol Group Acceptor)
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Jak1 protein, rat
  • Janus Kinase 1
  • Ribosomal Protein S6 Kinases
  • Immunophilins
  • Sirolimus