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Nat Commun. 2017 Mar 27;8:14892. doi: 10.1038/ncomms14892.

Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression.

Author information

1
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
2
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
3
German Institute of Human Nutrition, Central Regulation of Metabolism, Potsdam-Rehbrücke, 14558 Nuthetal, Germany.
4
National Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
6
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
7
Bioinformatics Core, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
8
Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.
9
Department of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
10
IMED Cardiovascular and Metabolic Diseases, AstraZeneca R&D, 43183 Mölndal, Sweden.

Abstract

Despite a high degree of homology, insulin receptor (IR) and IGF-1 receptor (IGF1R) mediate distinct cellular and physiological functions. Here, we demonstrate how domain differences between IR and IGF1R contribute to the distinct functions of these receptors using chimeric and site-mutated receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to their higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation. Strikingly, replacement of leucine973 in the juxtamembrane region of IR to phenylalanine, which is present in IGF1R, mimics many of these signalling and gene expression responses. Overall, we show that the distinct activities of the closely related IR and IGF1R are mediated by their intracellular juxtamembrane region and substrate binding to this region.

PMID:
28345670
PMCID:
PMC5378997
DOI:
10.1038/ncomms14892
[Indexed for MEDLINE]
Free PMC Article

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