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  • Title: Determinants of IGF-II influencing stability, receptor binding and activation.
    Author: Blyth A, Ortiz M, Merriman A, Delaine C, Forbes B.
    Journal: Sci Rep; 2022 Mar 18; 12(1):4695. PubMed ID: 35304516.
    Abstract:
    Insulin like growth factor II (IGF-II) is involved in metabolic and mitogenic signalling in mammalian cells and plays important roles in normal fetal development and postnatal growth. It is structurally similar to insulin and binds not only with high affinity to the type 1 insulin-like growth factor receptor (IGF-1R) but also to the insulin receptor isoform A (IR-A). As IGF-II expression is commonly upregulated in cancer and its signalling promotes cancer cell survival, an antagonist that blocks IGF-II action without perturbing insulin signalling would be invaluable. The high degree of structural homology between the IR and IGF-1R makes selectively targeting either receptor in the treatment of IGF-II-dependent cancers very challenging. However, there are sequence differences between insulin and IGF-II that convey receptor selectivity and influence binding affinity and signalling outcome. Insulin residue YB16 is a key residue involved in maintaining insulin stability, dimer formation and IR binding. Mutation of this residue to glutamine (as found in IGF-II) results in reduced binding affinity. In this study we sought to determine if the equivalent residue Q18 in IGF-II plays a similar role. We show through site-directed mutagenesis of Q18 that this residue contributes to IGF-II structural integrity, selectivity of IGF-1R/IR binding, but surprisingly does not influence IR-A signalling activation. These findings provide insights into a unique IGF-II residue that can influence receptor binding specificity whilst having little influence on signalling outcome.
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