**Understanding IGF-II Action through Insights into Receptor Binding and Activation**

**Andrew J. Blyth 1, Nicholas S. Kirk 2,3 and Briony E. Forbes 1,\***


Received: 18 September 2020; Accepted: 7 October 2020; Published: 12 October 2020

**Abstract:** The insulin-like growth factor (IGF) system regulates metabolic and mitogenic signaling through an intricate network of related receptors and hormones. IGF-II is one of several hormones within this system that primarily regulates mitogenic functions and is especially important during fetal growth and development. IGF-II is also found to be overexpressed in several cancer types, promoting growth and survival. It is also unique in the IGF system as it acts through both IGF-1R and insulin receptor isoform A (IR-A). Despite this, IGF-II is the least investigated ligand of the IGF system. This review will explore recent developments in IGF-II research including a structure of IGF-II bound to IGF-1R determined using cryo-electron microscopy (cryoEM). Comparisons are made with the structures of insulin and IGF-I bound to their cognate receptors. Finally discussed are outstanding questions in the mechanism of action of IGF-II with the goal of developing antagonists of IGF action in cancer.

**Keywords:** IGF-II; insulin-like growth factor; IGF-1R; insulin receptor; IR-A; structural studies; receptor activation
