The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Serine/Threonine Phosphorylation of IRS-1 Triggers Its Degradation
Abstract
Insulin receptor substrate (IRS)-1 protein expression is markedly reduced in many insulin-resistant states, although the mechanism for this downregulation is unclear. In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. In contrast, a glycogen synthase kinase 3 inhibitor, a mitogen-activated protein kinase/extracellular-regulated kinase inhibitor, and various protein kinase C inhibitors had no effect. Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. We propose that a rapamycin-dependent pathway participates as a negative regulator of IRS-1, increasing its serine/threonine phosphorylation, which triggers degradation. Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity.
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“Alterations in the early steps of insulin signaling have been recognized as an important component of many insulin-resistant states (10).”
BackgroundRole of IRS-2 in insulin and cytokine signalling
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Cited by
mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt
O'Reilly, K. E., Rojo, F., She, Q.-B., Solit, D., Mills, G. B., Smith, D., Lane, H., Hofmann, F., Hicklin, D. J., Ludwig, D. L., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2925 · Cited by 2,561
Positive and negative regulation of insulin signaling through IRS-1 phosphorylation
Gual, P., Le Marchand-Brustel, Y., & Tanti, J.-F. (2005) · Biochimie · doi:10.1016/j.biochi.2004.10.019 · Cited by 912
Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training
Roberts, C. K., Hevener, A. L., & Barnard, R. J. (2013) · Comprehensive Physiology · doi:10.1002/cphy.c110062 · Cited by 831
The Molecular Basis for Oxidative Stress-Induced Insulin Resistance
Evans, J. L., Maddux, B. A., & Goldfine, I. D. (2005) · Antioxidants & Redox Signaling · doi:10.1089/ars.2005.7.1040 · Cited by 587
The role of fatty acids in insulin resistance
Sears, B., & Perry, M. (2015) · Lipids in Health and Disease · doi:10.1186/s12944-015-0123-1 · Cited by 548
Metadata
- Authors
- Pederson, T. M., Kramer, D. L., & Rondinone, C. M.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2001-01-01
- Volume
- 50
- Issue
- 1
- Pages
- 24-31
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2135766812
- Cited by
- 300
- References
- 51
- FWCI
- 5.86
- Type
- journal article
- Language
- en
- Open access
- closed
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