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.

中文翻译：

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胰岛素样生长因子结合蛋白的信号传导途径。

6 种高亲和力胰岛素样生长因子结合蛋白 (IGFBP) 是多功能蛋白，可通过多种途径调节细胞信号传导。它们在细胞水平上的典型功能是阻止胰岛素样生长因子 (IGF)-1 和 IGF-2 接近其主要受体 IGF1R，但 IGFBP 也可以通过其自身的后信号抑制或有时增强 IGF1R 信号传导。翻译修饰，例如磷酸化或有限的蛋白水解，或通过它们与其他调节蛋白的相互作用。除了调节 IGF1R 活性之外，IGFBP 还被证明可以通过似乎不涉及 IGF-IGF1R 系统的机制来调节细胞存活、迁移、代谢和其他功能。这是通过与整合素、转化生长因子β家族受体和其他细胞表面蛋白以及作为多种途径中间体的细胞内配体直接或功能性相互作用来实现的。在细胞核内，IGFBP 可以调节 II 类核激素受体的多种功能，并通过非同源末端连接途径在细胞衰老和 DNA 损伤修复中发挥作用，从而可能改变某些癌症治疗的疗效。它们还调节一些免疫功能，并可能在类风湿性关节炎等自身免疫性疾病中发挥作用。IGFBP 已被认为是有吸引力的治疗靶点，但它们在循环和细胞水平上的普遍存在带来了许多挑战。通过了解 IGFBP 相互作用的调节途径的多样性，仍然可能存在基于 IGFBP 依赖性信号传导调节的治疗机会。