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A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression

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    0581691 - ÚOCHB 2025 RIV NL eng J - Journal Article
    Chrudinová, M. - Kirk, N. S. - Chuard, A. - Venugopal, H. - Zhang, F. - Lubos, Marta - Gelfanov, V. - Páníková, Terezie - Žáková, Lenka - Cutone, J. - Mojares, M. - DiMarchi, R. - Jiráček, Jiří - Altindis, E.
    A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression.
    Molecular Metabolism. Roč. 80, February (2024), č. článku 101863. ISSN 2212-8778. E-ISSN 2212-8778
    R&D Projects: GA MŠMT(CZ) LX22NPO5104
    Institutional support: RVO:61388963
    Keywords : viral insulin/IGF-1 like peptides (VILPs) * IGF-1 * insulin * IGF1 receptor * IGF1 receptor inhibition * biased signaling * Iridoviridae
    OECD category: Biochemistry and molecular biology
    Impact factor: 8.1, year: 2022
    Method of publishing: Open access
    https://doi.org/10.1016/j.molmet.2023.101863

    We identified five viruses containing genes encoding viral insulin/IGF-1 like peptides (VILPs). We chemically synthesized single chain (sc, IGF-1 like) and double chain (dc, insulin like) forms of MFRV and LCDV-Sa VILPs. VILPs can bind to human insulin and IGF1 receptors, stimulate receptor autophosphorylation and downstream signaling pathways. Notably, scMFRV VILP scMFRVVILP selectively reduced IGF-1 stimulated IGF1R autophosphorylation and Erk phosphorylation (Ras/MAPK pathway), while leaving Akt phosphorylation (PI3K/Akt pathway) unaffected, indicating a potential biased inhibitory function. Furthermore, insulin tolerance test revealed scMFRV VILP’s sustained glucose-lowering effect compared to insulin and IGF-1. Finally, cryo-EM analysis revealed that scMFRV-VILP engages with IGF1R in a manner closely resembling IGF-1 binding, resulting in a highly analogous structure. These findings offer valuable insights into IGF1R action and inhibition, suggesting potential applications in development of IGF1R specific inhibitors and advancing long-lasting insulins.
    Permanent Link: https://hdl.handle.net/11104/0349880

     
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    10.1016j.molmet.2023.101863.pdf14 MBPublisher’s postprintopen-access
     
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