TY - JOUR
T1 - Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
AU - Cai, Weikang
AU - Sakaguchi, Masaji
AU - Kleinridders, Andre
AU - Gonzalez-Del Pino, Gonzalo
AU - Dreyfuss, Jonathan M.
AU - O'Neill, Brian T.
AU - Ramirez, Alfred K.
AU - Pan, Hui
AU - Winnay, Jonathon N.
AU - Boucher, Jeremie
AU - Eck, Michael J.
AU - Kahn, C. Ronald
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/3/27
Y1 - 2017/3/27
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms14892
DO - 10.1038/ncomms14892
M3 - Article
C2 - 28345670
AN - SCOPUS:85016142286
SN - 2041-1723
VL - 8
JO - Nature Communications
JF - Nature Communications
M1 - 14892
ER -