title: Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression.
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 leucine973in 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.
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Weikang
authors.initials: W
authors.lastname: Cai
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Masaji
authors.initials: M
authors.lastname: Sakaguchi
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.|German Institute of Human Nutrition, Central Regulation of Metabolism, Potsdam-Rehbrücke, 14558 Nuthetal, Germany.|National Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Kleinridders
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gonzalez-Del Pino
authors.affiliation: Bioinformatics Core, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Dreyfuss
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: O'Neill
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Alfred K
authors.initials: AK
authors.lastname: Ramirez
authors.affiliation: Bioinformatics Core, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Pan
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Winnay
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.|IMED Cardiovascular and Metabolic Diseases, AstraZeneca R&D, 43183 Mölndal, Sweden.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Boucher
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D015870:Gene Expression; D005786:Gene Expression Regulation; D006019:Glycolysis; D007328:Insulin / Q000378:metabolism*; D007930:Leucine / Q000737:chemistry; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010649:Phenylalanine / Q000737:chemistry; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D010649:Phenylalanine; D017526:Receptor, IGF Type 1; D007930:Leucine