Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain

Adam Denley, Gemma V. Brierley, Julie M. Carroll, Anne Lindenberg, Grant W. Booker, Leah J. Cosgrove, John C. Wallace, Briony E. Forbes, Charles T. Roberts

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    33 Scopus citations

    Abstract

    The actions of IGF-I and IGF-II are thought to be largely due to their activation of the IGF-I receptor. However, IGF-II can also bind with high affinity to, and effectively activate, an isoform of the insulin receptor (IR-A) that lacks a sequence at the carboxyl-terminal end of the extracellular α subunit due to the alternative splicing of exon 11. This isoform is poorly activated by IGF-I. Here, we show that IGF-II, but not IGF-I, induces potent autophosphorylation of residues Y1158, Y1162, and Y1163 in the activation loop of the kinase domain and tyrosine 960 in the juxtamembrane region of both IR-A and IR-B (exon 11+) isoforms. We have also found, by using IGF chimeras, that the C domain of IGF-II completely accounts for the ability of IGF-II to stimulate IR autophosphorylation compared with IGF-I. We further show that the C domains are responsible for the differential abilities of IGF-II and IGF-I to activate phosphorylation of insulin receptor substrate-1 and Akt, as well as their ability to induce migration and cell survival via the IR-A. Finally, we show for the first time that IGF signaling through the IR-A can protect cells from butyrate-induced apoptosis. In summary, our studies define the structural determinants that allow potent IGF-II signaling and regulation of cellular functions through the IR-A and provide novel insights into IGF signaling via the IR.

    Original languageEnglish (US)
    Pages (from-to)1029-1036
    Number of pages8
    JournalEndocrinology
    Volume147
    Issue number2
    DOIs
    StatePublished - Feb 1 2006

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    ASJC Scopus subject areas

    • Endocrinology

    Cite this

    Denley, A., Brierley, G. V., Carroll, J. M., Lindenberg, A., Booker, G. W., Cosgrove, L. J., Wallace, J. C., Forbes, B. E., & Roberts, C. T. (2006). Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain. Endocrinology, 147(2), 1029-1036. https://doi.org/10.1210/en.2005-0736