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 Roberts

    Research output: Contribution to journalArticle

    31 Citations (Scopus)

    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 2006

    Fingerprint

    Insulin-Like Growth Factor II
    Insulin Receptor
    Somatomedins
    Protein Isoforms
    Insulin-Like Growth Factor I
    Exons
    Insulin Receptor Substrate Proteins
    IGF Type 1 Receptor
    Butyrates
    Alternative Splicing
    Protein-Tyrosine Kinases
    Cell Survival
    Phosphorylation
    Apoptosis

    ASJC Scopus subject areas

    • Endocrinology
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Denley, A., Brierley, G. V., Carroll, J. M., Lindenberg, A., Booker, G. W., Cosgrove, L. J., ... Roberts, C. (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

    Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain. / Denley, Adam; Brierley, Gemma V.; Carroll, Julie M.; Lindenberg, Anne; Booker, Grant W.; Cosgrove, Leah J.; Wallace, John C.; Forbes, Briony E.; Roberts, Charles.

    In: Endocrinology, Vol. 147, No. 2, 02.2006, p. 1029-1036.

    Research output: Contribution to journalArticle

    Denley, A, Brierley, GV, Carroll, JM, Lindenberg, A, Booker, GW, Cosgrove, LJ, Wallace, JC, Forbes, BE & Roberts, C 2006, 'Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain', Endocrinology, vol. 147, no. 2, pp. 1029-1036. https://doi.org/10.1210/en.2005-0736
    Denley A, Brierley GV, Carroll JM, Lindenberg A, Booker GW, Cosgrove LJ et al. Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain. Endocrinology. 2006 Feb;147(2):1029-1036. https://doi.org/10.1210/en.2005-0736
    Denley, Adam ; Brierley, Gemma V. ; Carroll, Julie M. ; Lindenberg, Anne ; Booker, Grant W. ; Cosgrove, Leah J. ; Wallace, John C. ; Forbes, Briony E. ; Roberts, Charles. / Differential activation of insulin receptor isoforms by insulin-like growth factors is determined by the C domain. In: Endocrinology. 2006 ; Vol. 147, No. 2. pp. 1029-1036.
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