Document Detail

Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1.
MedLine Citation:
PMID:  11809794     Owner:  NLM     Status:  MEDLINE    
Insulin receptor substrate 1 (IRS-1) plays an important role in the insulin signaling cascade. In vitro and in vivo studies from many investigators have suggested that lowering of IRS-1 cellular levels may be a mechanism of disordered insulin action (so-called insulin resistance). We previously reported that the protein levels of IRS-1 were selectively regulated by a proteasome degradation pathway in CHO/IR/IRS-1 cells and 3T3-L1 adipocytes during prolonged insulin exposure, whereas IRS-2 was unaffected. We have now studied the signaling events that are involved in activation of the IRS-1 proteasome degradation pathway. Additionally, we have addressed structural elements in IRS-1 versus IRS-2 that are required for its specific proteasome degradation. Using ts20 cells, which express a temperature-sensitive mutant of ubiquitin-activating enzyme E1, ubiquitination of IRS-1 was shown to be a prerequisite for insulin-induced IRS-1 proteasome degradation. Using IRS-1/IRS-2 chimeric proteins, the N-terminal region of IRS-1 including the PH and PTB domains was identified as essential for targeting IRS-1 to the ubiquitin-proteasome degradation pathway. Activation of phosphatidylinositol 3-kinase is necessary but not sufficient for activating and sustaining the IRS-1 ubiquitin-proteasome degradation pathway. In contrast, activation of mTOR is not required for IRS-1 degradation in CHO/IR cells. Thus, our data provide insight into the molecular mechanism of insulin-induced activation of the IRS-1 ubiquitin-proteasome degradation pathway.
Rachel Zhande; John J Mitchell; Jiong Wu; Xiao Jian Sun
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  22     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2002 Feb 
Date Detail:
Created Date:  2002-01-25     Completed Date:  2002-03-01     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1016-26     Citation Subset:  IM    
Endocrinology Division, University of Vermont College of Medicine, Burlington, Vermont 05405, USA.
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MeSH Terms
Antibiotics, Antineoplastic / pharmacology
CHO Cells
Chromones / pharmacology
Cysteine Endopeptidases / metabolism*
Enzyme Activation
Enzyme Inhibitors / pharmacology
Insulin / metabolism*,  pharmacology
Insulin Receptor Substrate Proteins
Morpholines / pharmacology
Multienzyme Complexes / metabolism*
Oligopeptides / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Phosphoproteins / genetics,  metabolism*
Proteasome Endopeptidase Complex
Protein Structure, Tertiary
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Receptor, Insulin / genetics,  metabolism
Recombinant Fusion Proteins / metabolism
Signal Transduction* / drug effects
Sirolimus / pharmacology
Ubiquitin / metabolism
Grant Support
Reg. No./Substance:
0/Antibiotics, Antineoplastic; 0/Chromones; 0/Enzyme Inhibitors; 0/IRS1 protein, human; 0/Insulin; 0/Insulin Receptor Substrate Proteins; 0/Morpholines; 0/Multienzyme Complexes; 0/Oligopeptides; 0/Phosphoproteins; 0/Proto-Oncogene Proteins; 0/Recombinant Fusion Proteins; 0/Ubiquitin; 134381-21-8/epoxomicin; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 53123-88-9/Sirolimus; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC, Insulin; EC Kinases; EC Proteins c-akt; EC 3.4.22.-/Cysteine Endopeptidases; EC Endopeptidase Complex

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