| A novel domain mediates insulin-induced proteasomal degradation of insulin receptor substrate 1 (IRS-1). | |
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MedLine Citation:
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PMID: 20843941 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Insulin receptor substrate-1 (IRS-1) plays a pivotal role in insulin signaling, therefore its degradation is exquisitely regulated. Here, we show that insulin-stimulated degradation of IRS-1 requires the presence of a highly conserved Ser/Thr-rich domain that we named domain involved in degradation of IRS-1 (DIDI). DIDI (amino acids 386-430 of IRS-1) was identified by comparing the intracellular degradation rate of several truncated forms of IRS-1 transfected into CHO cells. The isolated DIDI domain underwent insulin-stimulated Ser/Thr phosphorylation, suggesting that it serves as a target for IRS-1 kinases. The effects of deletion of DIDI were studied in Fao rat hepatoma and in CHO cells expressing Myc-IRS-1(WT) or Myc-IRS-1(Δ386-430). Deletion of DIDI maintained the ability of IRS-1(Δ386-434) to undergo ubiquitination while rendering it insensitive to insulin-induced proteasomal degradation, which affected IRS-1(WT) (80% at 8 h). Consequently, IRS-1(Δ386-434) mediated insulin signaling (activation of Akt and glycogen synthesis) better than IRS-1(WT). IRS-1(Δ386-434) exhibited a significant greater preference for nuclear localization, compared with IRS-1(WT). Higher nuclear localization was also observed when cells expressing IRS-1(WT) were incubated with the proteasome inhibitor MG-132. The sequence of DIDI is conserved more than 93% across species, from fish to mammals, as opposed to approximately 40% homology of the entire IRS-1. These findings implicate DIDI as a novel, highly conserved domain of IRS-1, which mediates its cellular localization, rate of degradation, and biological activity, with a direct impact on insulin signal transduction. |
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Authors:
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Sigalit Boura-Halfon; Timor Shuster-Meiseles; Avital Beck; Katia Petrovich; Diana Gurevitch; Denise Ronen; Yehiel Zick |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-15 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 24 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-28 Completed Date: 2011-02-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 2179-92 Citation Subset: IM |
Affiliation:
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Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects CHO Cells Cricetinae Cricetulus Cytoprotection / drug effects Insulin / pharmacology* Insulin Receptor Substrate Proteins / chemistry*, metabolism* Mice Mutant Proteins / chemistry, metabolism Phosphorylation / drug effects Phosphoserine / metabolism Proteasome Endopeptidase Complex / metabolism* Protein Processing, Post-Translational / drug effects* Protein Structure, Tertiary Protein Transport / drug effects Proto-Oncogene Proteins c-mdm2 / metabolism Rats Sequence Deletion Signal Transduction / drug effects Structure-Activity Relationship Ubiquitination / drug effects |
| Chemical | |
Reg. No./Substance:
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0/Insulin Receptor Substrate Proteins; 0/Mutant Proteins; 11061-68-0/Insulin; 17885-08-4/Phosphoserine; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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