Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked β-N-acetylglucosamine in 3T3-L1 adipocytes

Stephen A. Whelan, Wagner B. Dias, Lakshmanan Thiruneelakantapillai, M. Daniel Lane, Gerald Warren Hart

Research output: Contribution to journalArticle

Abstract

Increased O-linked β-N-acetylglucosamine (O-GlcNAc) is associated with insulin resistance in muscle and adipocytes. Upon insulin treatment of insulin-responsive adipocytes, O-GlcNAcylation of several proteins is increased. Key insulin signaling proteins, including IRS-1, IRS-2, and PDK1, are substrates for OGT, suggesting potential O-GlcNAc control points within the pathway. To elucidate the roles of O-GlcNAc in dampening insulin signaling (Vosseller, K., Wells, L., Lane, M. D., and Hart, G. W. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 5313-5318), we focused on the pathway upstream of AKT. Increasing O-GlcNAc in 3T3-L1 adipocytes decreases phosphoinositide 3-kinase (PI3K) interactions with both IRS-1 and IRS-2. Elevated O-GlcNAc also reduces phosphorylation of the PI3K p85 binding motifs (YXXM) of IRS-1 and results in a concomitant reduction in tyrosine phosphorylation of Y608XXM in IRS-1, one of the two main PI3K p85 binding motifs. Additionally, insulin signaling stimulates the interaction of OGT with PDK1. We conclude that one of the steps at which O-GlcNAc contributes to insulin resistance is by inhibiting phosphorylation at the Y608XXM PI3K p85 binding motif in IRS-1 and possibly at PDK1 as well.

Original languageEnglish (US)
Pages (from-to)5204-5211
Number of pages8
JournalJournal of Biological Chemistry
Volume285
Issue number8
DOIs
StatePublished - Feb 19 2010

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Insulin Receptor Substrate Proteins
Acetylglucosamine
Adipocytes
1-Phosphatidylinositol 4-Kinase
Phosphotransferases
Insulin
Phosphatidylinositols
Phosphorylation
Insulin Resistance
Tyrosine
Muscles
Muscle
Proteins
Substrates

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked β-N-acetylglucosamine in 3T3-L1 adipocytes. / Whelan, Stephen A.; Dias, Wagner B.; Thiruneelakantapillai, Lakshmanan; Daniel Lane, M.; Hart, Gerald Warren.

In: Journal of Biological Chemistry, Vol. 285, No. 8, 19.02.2010, p. 5204-5211.

Research output: Contribution to journalArticle

Whelan, Stephen A. ; Dias, Wagner B. ; Thiruneelakantapillai, Lakshmanan ; Daniel Lane, M. ; Hart, Gerald Warren. / Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked β-N-acetylglucosamine in 3T3-L1 adipocytes. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 8. pp. 5204-5211.
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