Document Detail


Substitution of isoleucine for methionine at position 1153 in the beta-subunit of the human insulin receptor. A mutation that impairs receptor tyrosine kinase activity, receptor endocytosis, and insulin action.
MedLine Citation:
PMID:  1314826     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The intracellular domain of the insulin receptor possesses activity as a tyrosine-specific protein kinase. The receptor tyrosine kinase is stimulated by insulin binding to the extracellular domain of the receptor. Previously, we have identified a patient with a genetic form of insulin resistance who is heterozygous for a mutation substituting Ile for Met1153 in the tyrosine kinase domain of the receptor near the cluster of the three major autophosphorylation sites (Tyr1158, Tyr1162, and Tyr1163). In this investigation, the Ile1153 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells. The mutation impairs receptor tyrosine kinase activity and also inhibits the ability of insulin to stimulate 2-deoxyglucose uptake and thymidine incorporation. These data support the hypothesis that the receptor tyrosine activity plays a necessary role in the ability of the receptor to mediate insulin action in vivo. Furthermore, expression of the Ile1153 mutant receptor exerted a dominant negative effect to inhibit the ability of endogenous murine receptors for insulin and insulin-like growth factor I to mediate their actions upon the cell. This observation is consistent with previous suggestions that mutant receptors dimerize with wild type receptors, thereby creating hybrid molecules which lack biological activity. The dominant negative effect of the mutant receptor may explain the dominant mode of inheritance of insulin resistance caused by the Ile1153 mutation. Finally, the mutation inhibits the ability of insulin to stimulate receptor endocytosis. This may explain the normal number of insulin receptors on the surface of the patient's cells in vivo. Despite the presence of markedly elevated levels of insulin in the patient's plasma, the receptors were resistant to down-regulation.
Authors:
A Cama; M J Quon; M de la Luz Sierra; S I Taylor
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  267     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1992 Apr 
Date Detail:
Created Date:  1992-05-28     Completed Date:  1992-05-28     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  8383-9     Citation Subset:  IM    
Affiliation:
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland 20892.
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MeSH Terms
Descriptor/Qualifier:
3T3 Cells
Animals
DNA / genetics
Endocytosis*
Enzyme Activation
Female
Heterozygote
Humans
Insulin / pharmacology*
Insulin-Like Growth Factor I / metabolism,  pharmacology
Isoleucine / genetics*
Methionine / genetics*
Mice
Mutation*
Phosphorylation
Protein-Tyrosine Kinases / metabolism*
Receptor, Insulin / genetics*,  metabolism
Transfection
Chemical
Reg. No./Substance:
11061-68-0/Insulin; 63-68-3/Methionine; 67763-96-6/Insulin-Like Growth Factor I; 73-32-5/Isoleucine; 9007-49-2/DNA; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, Insulin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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