Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes

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...

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Veröffentlicht in:The Journal of biological chemistry 2010-02, Vol.285 (8), p.5204
Hauptverfasser: Stephen A. Whelan, Wagner B. Dias, Lakshmanan Thiruneelakantapillai, M. Daniel Lane, Gerald W. Hart
Format: Artikel
Sprache:eng
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Zusammenfassung: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 (Y XX M) of IRS-1 and results in a concomitant reduction in tyrosine phosphorylation of Y 608 XX M 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 Y 608 XX M PI3K p85 binding motif in IRS-1 and possibly at PDK1 as well.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.077818