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Cited by 640Metabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase SignalingGrowth Hormone and Insulin-like Growth Factors

Human insulin receptors mutated at the ATP-binding site lack protein tyrosine kinase activity and fail to mediate postreceptor effects of insulin.

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Chou, C K, Dull, T J, Russell, D S, Gherzi, R, Lebwohl, D, Ullrich, A, Rosen, O M·1987·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(19)75716-0
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Abstract

Transfected Chinese hamster ovary cell lines were developed that expressed equivalent numbers of either normal human receptor or receptor that had alanine substituted for Lys-1018 in the ATP-binding domain of the beta subunit. The mutated receptor was processed into subunits and bound insulin but lacked protein tyrosine kinase activity. Five effects of insulin were assayed: deoxyglucose uptake, S6 kinase activity, endogenous protein-tyrosine phosphorylation, glycogen synthesis, and thymidine uptake. In each case, cells bearing normal human receptors were 10-100-fold more sensitive to insulin than the parental cells. Cells with the mutant receptor behaved like the parental cells with respect to S6 kinase activation, endogenous substrate phosphorylation, glycogen synthesis, and thymidine uptake, but their deoxyglucose uptake was significantly depressed and relatively insensitive to insulin. The analyses led to the following conclusions: substitution of alanine for lysine at amino acid 1018 inactivates the kinase activity of the receptor; a kinase-negative receptor can be properly processed and bind insulin; insulin-dependent deoxyglucose uptake, S6 kinase activation, endogenous substrate phosphorylation, glycogen synthesis, and thymidine incorporation into DNA are mediated by the normal but not by the kinase-deficient human receptor.

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  • Mutation of specific tyrosine residues in IRS-1 severely impairs insulin stimulation of muscle glycogen synthesis, glucose uptake and oxidation, and other metabolic and growth-promoting effects.

    “Mutation of these specific tyrosine residues in IRS-1 severely impairs the ability of insulin to stimulate muscle glycogen synthesis, glucose uptake and oxidation, and other acute metabolic- and growth-promoting effects of insulin [142].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [142]

  • Mutagenesis of any of the three major phosphorylation sites (residues 1158, 1163, and 1162) impairs insulin receptor tyrosine kinase activity, decreasing metabolic and growth-promoting effects of insulin.

    “Mutagenesis of any of the three major phosphorylation sites (at residues 1158, 1163, and 1162) impairs insulin receptor tyrosine kinase activity, leading to a decrease in the metabolic and growth-promoting effects of insulin [141, 142].”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [142]

  • PI3K inhibitors impair glucose transport and block activation of glycogen synthase and HK-II expression.

    “Inhibitors of PI3K impair glucose transport and block the activation of glycogen synthase and hexokinase- (HK-) II expression [138–146]”

    From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [142]

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Authors
Chou, C. K., Dull, T. J., Russell, D. S., Gherzi, R., Lebwohl, D., Ullrich, A., & Rosen, O. M.
Affiliations
  • Cornell University (US)
  • Ospedale Policlinico San Martino (IT)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1987-02
Volume
262
Issue
4
Pages
1842-1847
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(19)75716-0
OpenAlex
W1533778697
Cited by
640
References
35
Citations by year
2025: 2 · 2024: 1 · 2021: 7 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 4 · 2015: 5 · 2014: 2 · 2013: 3 · 2012: 5
FWCI
38.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01am035158-02)
  • National Institute of General Medical Sciences (GM 34555)
  • Fogarty International Center (TWO 3698)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
insulin receptor, ATP binding site, alanine substitution, protein tyrosine kinase activity, 2-deoxyglucose uptake, S6 kinase, tyrosine phosphorylation, glycogen synthesis, thymidine incorporation, receptor processing, insulin sensitivity
MeSH terms
Adenosine Triphosphate, Animals, Cell Line, Cricetulus, Deoxyglucose, Glycogen, Cricetinae, Humans, Insulin, Lysine, Methionine, Mutation, Phosphorylation, Protein-Tyrosine Kinases, Receptor, Insulin, Thymidine, Transfection

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