SEARCHNARRATIVE_REVIEWbiomedical research, preclinical research

narrative_review·biomedical research, preclinical research, endocrinology, research methods·PMC10502586

Signaling Pathways of the Insulin-like Growth Factor Binding Proteins

Endocrine Reviews · 1 author, 1 centre

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This is a narrative review discussing the multiple ways IGF binding proteins (IGFBPs) can impact cellular functions through both IGF receptor-mediated and IGF-independent signaling pathways.

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The paper describes the structure and function of IGF-1, IGF-2, and their receptors, emphasizing the IGF1R as a key signaling molecule. The central focus is on the expanding understanding that IGFBPs have actions independent of IGF binding, influencing cell signaling through various ligands and pathways. The review notes that knowledge of the specific protein-protein interactions for IGFBP signaling is still in an early stage, with many interactions likely regulated by post-translational modifications. The implications are that a better understanding of IGFBP-ligand interactions could present new opportunities to modulate disease development or progression.

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narrative_review

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biomedical research

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ORIGINAL PAPER

PMC10502586

Signaling Pathways of the Insulin-like Growth Factor Binding Proteins

Endocrine Reviews

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ABSTRACT

Abstract The 6 high-affinity insulin-like growth factor binding proteins (IGFBPs) are multifunctional proteins that modulate cell signaling through multiple pathways. Their canonical function at the cellular level is to impede access of insulin-like growth factor (IGF)-1 and IGF-2 to their principal receptor IGF1R, but IGFBPs can also inhibit, or sometimes enhance, IGF1R signaling either through their own post-translational modifications, such as phosphorylation or limited proteolysis, or by their interactions with other regulatory proteins. Beyond the regulation of IGF1R activity, IGFBPs have been shown to modulate cell survival, migration, metabolism, and other functions through mechanisms that do not appear to involve the IGF-IGF1R system. This is achieved by interacting directly or functionally with integrins, transforming growth factor β family receptors, and other cell-surface proteins as well as intracellular ligands that are intermediates in a wide range of pathways. Within the nucleus, IGFBPs can regulate the diverse range of functions of class II nuclear hormone receptors and have roles in both cell senescence and DNA damage repair by the nonhomologous end-joining pathway, thus potentially modifying the efficacy of certain cancer therapeutics. They also modulate some immune functions and may have a role in autoimmune conditions such as rheumatoid arthritis. IGFBPs have been proposed as attractive therapeutic targets, but their ubiquity in the circulation and at the cellular level raises many challenges. By understanding the diversity of regulatory pathways with which IGFBPs interact, there may still be therapeutic opportunities based on modulation of IGFBP-dependent signaling. Keywords: IGF, IGF binding protein, signaling, receptor, cell-surface, nucleus

CITATION EXPORT

Robert C Baxter. Signaling Pathways of the Insulin-like Growth Factor Binding Proteins. Endocrine Reviews. (2023). https://doi.org/10.1210/endrev/bnad008

AUTHORS

1 · 1 CENTRES

Robert C Baxter

1 Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, NSW 2065, Australia