The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 *

By Vincent Aguirre, T. Uchida, L. Yenush, R. Davis, M. White. Journal of Biological Chemistry, 2000

1,137 citations recorded by the source corpus.

Tumor necrosis factor α (TNFα) inhibits insulin action, in part, through serine phosphorylation of IRS proteins; however, the phosphorylation sites that mediate the inhibition are unknown. TNFα promotes multipotential signal transduction cascades, including the activation of the Jun NH2-terminal kinase (JNK). Endogenous JNK associates with IRS-1 in Chinese hamster ovary cells. Anisomycin, a strong activator of JNK in these cells, stimulates the activity of JNK bound to IRS-1 and inhibits the insulin-stimulated tyrosine phosphorylation of IRS-1. Serine 307 is a major site of JNK phosphorylation in IRS-1. Mutation of serine 307 to alanine eliminates phosphorylation of IRS-1 by JNK and abrogates the inhibitory effect of TNFα on insulin-stimulated tyrosine phosphorylation of IRS-1. These results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFα on IRS-1 function.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/985014e19d5e563caf8cfef3d10c2ce6a5d9ca40

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Citations in the corpus

Mechanisms of insulin resistance in obesity (2013, background): “The activity of JNK was first found in the pathogenesis of insulin resistance for phosphorylation of IRS-1 S307 (S312 in human), which inhibits the insulin signaling pathway in response to TNF-α signal [13,18].”
A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. (2006, neutral): “Furthermore, levels of free p85 also impact the activation of regulatory phosphatases (Gupta et al., 1999) and Jnk (Aguirre et al., 2000; Ueki et al., 2002), which participate in the complex regulation of PI3 kinase signaling.”
Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links (2012, positive): “…that the defect in insulin signaling can be attributed to serine phosphorylation of IRS1 at serine-307 residue by activation of jun-N-terminal kinase 1 (JNK1), providing a plausible mechanistic link between inﬂammation and insulin resistance (Aguirre et al., 2000; Hotamisligil et al., 1996).”
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 (2012, methodology): “Treatment of CHO cells with the low-specificity JNK agonist anisomycin was used to identify S307 (hS312) near the IRS1 PTB domain as a major site of phosphorylation [38].”
MAP kinases and cell migration (2004, background): “…et al., 2003; Gdalyahu et al., 2004; Neidhart et al., 2001), the actin-binding protein spir (Otto et al., 2000), the protein kinase p90RSK (Zhang et al., 2001), and the adaptors insulin receptor substrate 1 (Irs-1), p66ShcA and paxillin (Aguirre et al., 2000; Huang et al., 2003; Le et al., 2001).”
Inflammation, stress, and diabetes. (2005, neutral): “upon it associates with and phosphorylates IRS-1 on Ser307, impairing insulin action (36, 39, 48).”
Mechanisms of obesity-associated insulin resistance: many choices on the menu. (2007, background): “The kinases that have been shown to be activated by oxidative stress include JNK, p38 MAPK, and IKK (Blair et al. 1999; Aguirre et al. 2000; Maddux et al. 2001; Yuan et al. 2001; Hirosumi et al. 2002).”