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

Author

Listed:
  • Weikang Cai

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School)

  • Masaji Sakaguchi

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School)

  • Andre Kleinridders

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School
    German Institute of Human Nutrition, Central Regulation of Metabolism, Potsdam-Rehbrücke
    National Center for Diabetes Research (DZD))

  • Gonzalo Gonzalez-Del Pino

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Jonathan M. Dreyfuss

    (Bioinformatics Core, Joslin Diabetes Center
    Boston University)

  • Brian T. O’Neill

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School
    Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine)

  • Alfred K. Ramirez

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School
    Boston University)

  • Hui Pan

    (Bioinformatics Core, Joslin Diabetes Center
    Boston University)

  • Jonathon N. Winnay

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School)

  • Jeremie Boucher

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School
    IMED Cardiovascular and Metabolic Diseases, AstraZeneca R&D)

  • Michael J. Eck

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • C. Ronald Kahn

    (Section of Integrative Physiology and Metabolism, Joslin Diabetes Center
    Harvard Medical School)

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.

Suggested Citation

  • Weikang Cai & Masaji Sakaguchi & Andre Kleinridders & Gonzalo Gonzalez-Del Pino & Jonathan M. Dreyfuss & Brian T. O’Neill & Alfred K. Ramirez & Hui Pan & Jonathon N. Winnay & Jeremie Boucher & Michael, 2017. "Domain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14892
    DOI: 10.1038/ncomms14892
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    Cited by:

    1. Lu Guang & Shilin Ma & Ziyue Yao & Dan Song & Yu Chen & Shuqing Liu & Peng Wang & Jiali Su & Yuefan Wang & Lanfang Luo & Ng Shyh-Chang, 2025. "An obesogenic FTO allele causes accelerated development, growth and insulin resistance in human skeletal muscle cells," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    2. Hirofumi Nagao & Ashok Kumar Jayavelu & Weikang Cai & Hui Pan & Jonathan M. Dreyfuss & Thiago M. Batista & Bruna B. Brandão & Matthias Mann & C. Ronald Kahn, 2023. "Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Francois Moreau & Nicholas S. Kirk & Fa Zhang & Vasily Gelfanov & Edward O. List & Martina Chrudinová & Hari Venugopal & Michael C. Lawrence & Veronica Jimenez & Fatima Bosch & John J. Kopchick & Rich, 2022. "Interaction of a viral insulin-like peptide with the IGF-1 receptor produces a natural antagonist," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Masaji Sakaguchi & Shota Okagawa & Yuma Okubo & Yuri Otsuka & Kazuki Fukuda & Motoyuki Igata & Tatsuya Kondo & Yoshifumi Sato & Tatsuya Yoshizawa & Takaichi Fukuda & Kazuya Yamagata & Weikang Cai & Yu, 2022. "Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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