Sites within the early steps of the insulin signaling pathway affected by OGT and O-GlcNAcylation

Sites within the early steps of the insulin signaling pathway affected by OGT and O-GlcNAcylation. Upon insulin treatment of 3T3-L1 adipocytes, OGT is recruited to the insulin receptor (IR), tyrosine-phosphorylated, and catalytically activated () (1). OGT in turn modifies proteins, such as transcription factors (Sp1 and STAT3) (2) and kinases (PDK1), as well as a potential host of other unknown proteins (3). Acute insulin stimulation induces OGT interaction with at least PDK1 in the insulin signaling pathway and an increase in O-GlcNAc modification (4). Elevation of O-GlcNAc induced by PUGNAc inhibits OGT interaction with PDK1. Wortmannin (5) is a general inhibitor of PI3K, which blocks downstream AKT activation (6). During normal insulin-stimulated insulin receptor/AKT signaling, the insulin receptor becomes activated and phosphorylates the IRS-1 and IRS-2 YXXM motifs (Y608XXM and Y628XXM), which recruit and activate PI3K p85, resulting in downstream activation of PDK1, which in turn phosphorylates AKT (Thr308), resulting in GLUT-4 glucose uptake (7). Elevations in O-GlcNAc specifically induced by the O-GlcNAcase inhibitor PUGNAc result in O-GlcNAc modification of IRS-1 and decreased phosphorylation of Y608XXM (8), decreased PI3K p85 interaction with IRS-1, and downstream reduced phosphorylation of Thr308 of AKT, resulting in reduced GLUT-4 glucose uptake. IRS-1, IRS-2, and PDK1 were all excellent substrates for OGT in vitro (9). O-GlcNAc modification of PDK1 may play a role in reduced AKT activation.

Publication

Regulation of Insulin Receptor Substrate 1 (IRS-1)/AKT Kinase-mediated Insulin Signaling by O-Linked β-N-Acetylglucosamine in 3T3-L1 Adipocytes. (2010) Stephen A. Whelan, et al. J Biol Chem. 2010 Feb 19;285(8):5204-5211. Figure: F6. All organisms Homo sapiens Mus musculus Danio rerio

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