Editors' ChoicePathway Interactions

IRS Depleted by Dirty SOCS

+ See all authors and affiliations

Science's STKE  05 Nov 2002:
Vol. 2002, Issue 157, pp. tw402-TW402
DOI: 10.1126/stke.2002.157.tw402

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]

Related Content