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. 2021 Mar 22;9:641449. doi: 10.3389/fcell.2021.641449

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Copyright © 2021 Ianza, Sirico, Bernocchi and Generali.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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A schematic diagram of insulin growth factor-1 receptor (IGF-IR) activation and regulation. The IGF axis consists of ligands as insulin, insulin-like growth factor 1 and 2 (IGF-1, IGF-2), receptor, IGF binding proteins (IGFBPs) 1–7, and IGFBP proteases. The IGF ligands bind their receptors and binding proteins with high affinity. IGFBPs bind tightly to IGF ligands, influencing binding to their receptors; IGFBP proteases cleave the IGFBPs into fragments with lower affinity for the IGF ligands, thereby increasing free IGF-1 and IGF-2 bioavailability. Activation of IGF-1R promotes cellular growth, proliferation, survival, and metastasis via activation of molecular pathways downstream; among them the phosphatidylinositol 3-kinase (PI3K)-AKT and RAS-extracellular signal-regulated kinase (ERK) pathways.