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 - Jan 1 2001

Fingerprint

TOR Serine-Threonine Kinases
Insulin Receptor Substrate Proteins
Phosphorylation
Serine
Tyrosine
Interferons
70-kDa Ribosomal Protein S6 Kinases
Janus Kinases
Protein-Serine-Threonine Kinases
Sirolimus
Phosphotransferases

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

FRAP-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation. / Hartman, M. E.; Villela-Bach, M.; Chen, J.; Freund, G. G.

In: Biochemical and Biophysical Research Communications, Vol. 280, No. 3, 94214, 01.01.2001, p. 776-781.

Research output: Contribution to journalArticle

@article{7ef1177b9ac049dd83dee561be045383,
title = "FRAP-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation",
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.",
keywords = "Cytokine resistance, FRAP, IFNα, IRS-1, JAK1, RAFT1, Rapamycin, Serine phosphorylation, mTOR, p70",
author = "Hartman, {M. E.} and M. Villela-Bach and J. Chen and Freund, {G. G.}",
year = "2001",
month = "1",
day = "1",
doi = "10.1006/bbrc.2000.4214",
language = "English (US)",
volume = "280",
pages = "776--781",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - FRAP-dependent serine phosphorylation of IRS-1 inhibits IRS-1 tyrosine phosphorylation

AU - Hartman, M. E.

AU - Villela-Bach, M.

AU - Chen, J.

AU - Freund, G. G.

PY - 2001/1/1

Y1 - 2001/1/1

N2 - 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.

AB - 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.

KW - Cytokine resistance

KW - FRAP

KW - IFNα

KW - IRS-1

KW - JAK1

KW - RAFT1

KW - Rapamycin

KW - Serine phosphorylation

KW - mTOR

KW - p70

UR - http://www.scopus.com/inward/record.url?scp=0034816272&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034816272&partnerID=8YFLogxK

U2 - 10.1006/bbrc.2000.4214

DO - 10.1006/bbrc.2000.4214

M3 - Article

C2 - 11162588

AN - SCOPUS:0034816272

VL - 280

SP - 776

EP - 781

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

M1 - 94214

ER -