Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts 02215, USA.
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nat Commun. 2017 Mar 27;8:14892. doi: 10.1038/ncomms14892.
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 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.
尽管胰岛素受体 (IR) 和 IGF-1 受体 (IGF1R) 具有高度同源性，但它们介导不同的细胞和生理功能。在这里，我们使用嵌合和位点突变受体证明了 IR 和 IGF1R 之间的结构域差异如何导致这些受体的不同功能。具有 IGF1R 细胞内结构域的受体显示出 Shc 和 Gab-1 的激活增加，以及与增殖相关的基因的更有效调节，这与其更高的有丝分裂活性相对应。相反，具有 IR 细胞内结构域的受体显示出 IRS-1 磷酸化更高，代谢途径中的基因调节更强，以及对激素刺激的糖酵解反应更明显。引人注目的是，将 IR 中近膜区的亮氨酸替换为 IGF1R 中存在的苯丙氨酸，可模拟许多这些信号转导和基因表达反应。总的来说，我们表明，密切相关的 IR 和 IGF1R 的不同活性是由它们的细胞内近膜区及其与该区域的底物结合介导的。
