Journal article
Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
Nature communications, Vol.8(1), pp.14892-14892
03/27/2017
DOI: 10.1038/ncomms14892
PMCID: PMC5378997
PMID: 28345670
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 leucine(973) 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.
Details
- Title: Subtitle
- Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
- Creators
- Weikang Cai - Joslin Diabetes CenterMasaji Sakaguchi - Joslin Diabetes CenterAndre Kleinridders - Joslin Diabetes CenterGonzalo Gonzalez-Del Pino - Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USAJonathan M. Dreyfuss - Joslin Diabetes CenterBrian T. O'Neill - Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02215 USAAlfred K. Ramirez - Joslin Diabetes CenterHui Pan - Joslin Diabetes CenterJonathon N. Winnay - Joslin Diabetes CenterJeremie Boucher - Harvard UniversityMichael J. Eck - Dana-Farber Cancer InstituteC. Ronald Kahn - Harvard University
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.8(1), pp.14892-14892
- DOI
- 10.1038/ncomms14892
- PMID
- 28345670
- PMCID
- PMC5378997
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Springer Nature
- Number of pages
- 14
- Grant note
- Japan Society for the Promotion of Science; Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) R37DK031036 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Kl2399-4/1 / German Research Foundation (DFG) R01 DK031036; R01 DK033201; T32 DK007260-37; K08 DK100543 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 01GI092 / Federal Ministry of Education and Research (German Center for Diabetes Research) Manpei Suzuki Diabetes Foundation P30 DK36836 / The Joslin Diabetes Center DRC Genomics and Bioinformatics Core
- Language
- English
- Date published
- 03/27/2017
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359890202771
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