IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance
- G. Hotamisligil, P. Peraldi, A. Budavari, Ramsey Ellis, M. White, B. Spiegelman
- Biology, MedicineScience
- 2 February 1996
Results indicate that TNF-α induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.
Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle*
- Chunli Yu, Yan Chen, G. Shulman
- Biology, Computer ScienceJournal of Biological Chemistry
- 27 December 2002
The hypothesis that an increase in plasma fatty acid concentration results in a increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-θ leading to increased IRS-1 Ser307 phosphorylation is supported.
Disruption of IRS-2 causes type 2 diabetes in mice
- D. Withers, Julio Gutiérrez, M. White
- Biology, MedicineNature
- 26 February 1998
It is shown that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic β-cell function, indicating that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.
The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 *
- V. Aguirre, T. Uchida, L. Yenush, R. Davis, M. White
- Biology, ChemistryJournal of Biological Chemistry
- 24 March 2000
Results suggest that phosphorylation of serine 307 might mediate, at least partially, the inhibitory effect of proinflammatory cytokines like TNFα on IRS-1 function.
IRS proteins and the common path to diabetes.
- M. White
- BiologyAmerican Journal of Physiology. Endocrinology and…
- 1 September 2002
The broad role of IRS-1 and IRS-2 in cell growth and survival reveals a common regulatory pathway linking development, somatic growth, fertility, neuronal proliferation, and aging to the core mechanisms used by vertebrates for nutrient sensing.
Phosphorylation of Ser307 in Insulin Receptor Substrate-1 Blocks Interactions with the Insulin Receptor and Inhibits Insulin Action*
- V. Aguirre, E. Werner, J. Giraud, Y. Lee, S. Shoelson, M. White
- Biology, Computer ScienceJournal of Biological Chemistry
- 11 January 2002
In 32D myeloid progenitor cells, phosphorylation of Ser307 inhibited insulin stimulation of the phosphatidylinositol 3-kinase and MAPK cascades, suggesting that inhibition of PTB domain function in IRS-1 by phosphorylated Ser307 might be a general mechanism to regulate insulin signaling.
Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein
- X. Sun, P. Rothenberg, M. White
- Biology, Computer ScienceNature
- 4 July 1991
During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS–1 acts as a multisite Mocking' protein to bind signal-transducing molecules containing Src-homology 2 and SRC-Homology-3 domains, which may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
SOCS-1 and SOCS-3 Block Insulin Signaling by Ubiquitin-mediated Degradation of IRS1 and IRS2*
- L. Rui, M. Yuan, Daniel F Frantz, S. Shoelson, M. White
- BiologyJournal of Biological Chemistry
- 1 November 2002
SOCS-mediated degradation of IRS proteins, presumably via the elongin BC ubiquitin-ligase, might be a general mechanism of inflammation-induced insulin resistance, providing a target for therapy.
The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth.
- T. Kitamura, J. Nakae, D. Accili
- BiologyJournal of Clinical Investigation
- 15 December 2002
It is proposed that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.
...
...