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.
Highlights
The insulin-like growth factor (IGF) system controls metabolic and mitogenic responses in mammalian cells and importantly regulates embryonic growth and development as well as adult growth [1]
IGF-II plays a fundamental role in mammalian growth and fetal development
While IGF-II is the least investigated ligand of the IGF system, the recently determined structure of IGF-II bound to IGF-1R has certainly advanced our understanding of the mechanism of IGF-II binding and activation
Summary
The insulin-like growth factor (IGF) system controls metabolic and mitogenic responses in mammalian cells and importantly regulates embryonic growth and development as well as adult growth [1]. IGF-II is most abundant in the fetal and adult brain, primarily produced by the choroid plexus and the leptomeninges and endothelial cells [19,20,21,22,23]. IGF-II:IR-A signaling supports neural stem cell maintenance and the expansion of neural progenitor cells [27] This role in stem cell renewal extends to other tissues, as identified using stem cell specific knockout of Igf in young adults in which growth of intestinal stem cells is inhibited [28]. The type 2 IGF receptor (IGF-2R, called cation-independent mannose-6-phosphate receptor) is responsible for the control of circulating IGF-II levels, by binding to IGF-II with high affinity and targeting it for lysosomal degradation [30,31]
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