Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Sci. STKE, 5 November 2002
Vol. 2002, Issue 157, p. tw402
[DOI: 10.1126/stke.2002.157.tw402]

EDITORS' CHOICE

Pathway Interactions IRS Depleted by Dirty SOCS

Resistance to the metabolic effects of insulin is a problem not only in diabetes, but also in obesity and other situations of physiological stress. Increased production of proinflammatory cytokines associated with such stress is thought to contribute to insulin resistance. Rui et al. report a mechanism by which signals from cytokines may blunt insulin signaling. Proinflammatory cytokines cause increased expression of supressors of cytokine signaling (SOCS) proteins, which bind to cytokine receptors and associated JAK protein kinases. The SOCS proteins inhibit cytokine signaling in part by promoting ubiquitin-dependent degradation of JAKs. Now evidence is accumulating that SOCS protein may also modulate signaling by the insulin receptor tyrosine kinase. Rui et al. show that, in transfected cells, SOCS1 and SOCS3 bind to the insulin receptor substrate proteins IRS1 and IRS2, which link the insulin receptor to multiple intracellular signaling pathways. Adenoviral-induced expression of SOCS1 in mice reduced the abundance of IRS1 and IRS2 in liver and caused fasting hyperglycemia characteristic of insulin resistance. These effects were not observed if SOCS mutants were expressed in which interaction of SOCS with elongin B and elongin C and formation an E3 ubiquitin ligase complex was disrupted. Thus, targeting of IRS proteins for degradation may be a critical event in inflammation-induced insensitivity to insulin and could represent a therapeutic target for modulating deleterious effects of inflammatory cytokines.

L. Rui, M. Yuan, D. Frantz, S. Shoelson, M. F. White, SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42394-42398 (2002). [Abstract] [Full Text]

Citation: IRS Depleted by Dirty SOCS. Sci. STKE 2002, tw402 (2002).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882