Abstract
The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are dimeric disulfide-linked receptor tyrosine kinases, whose actions regulate metabolic and mitogenic signalling pathways inside the cell. It is well documented that in tissues co-expressing the IR and IGF1R, their respective monomers can heterodimerise to form IR–IGF1R hybrid receptors. Increased populations of the IR–IGF1R hybrid receptors are associated with several disease states, including type 2 diabetes and cancer. Recently, progress in the structural biology of IR and IGF1R has given insights into their structure–function relationships and mechanism of action. However, challenges in isolating IR–IGF1R hybrid receptors mean that their structural properties remain relatively unexplored. This review discusses the advances in the structural understanding of the IR and IGF1R, and how these discoveries can inform the design of small-molecule modulators of the IR–IGF1R hybrid receptors to understand their role in cell biology.
Highlights
The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are dimeric disulfide-linked receptor tyrosine kinases, whose actions regulate metabolic and mitogenic signalling pathways inside the cell
In endothelial cells Akt activates the endothelial isoform of nitric oxide synthase by phosphorylation of serine 1177.26,27 In humans and other mammals despite high structural homology and activation of similar downstream pathways the biological processes regulated by insulin and IGF-1 are strikingly different.[28]
The IR is activated through binding to insulin, whilst IGF1R is activated through binding to the hormones insulin-like growth factor (IGF) 1 and IGF2.34 Upon binding to their respective ligands, IR primarily regulates metabolic signalling through the PI3K/AKT pathway, whilst IGF1R elicits mitogenic effects through the Ras/ERK pathway
Summary
The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are dimeric disulfide-linked receptor tyrosine kinases, whose actions regulate metabolic and mitogenic signalling pathways inside the cell. The structural basis of activation of the insulin family receptors is still not fully understood, recent findings have significantly contributed towards providing a plausible activation mechanism of the receptors.[39] Ligands binding to the extracellular portion (ectodomain) of the receptors affect trans-autophosphorylation of the intracellular kinase domains, which in turn promotes binding and phosphorylation of adaptor proteins to affect subsequent downstream signalling. Due to their high homology, the IR and IGF1R can heterodimerise to form functional hybrid receptors in tissues in which they are co-expressed, consisting of an IR monomer and IGF1R monomer. While the role of hybrids in human physiology is undefined there is a clear association with increased hybrids and situations of metabolic stress including: type 2 diabetes mellitus,[44,45] obesity,[46] hyperinsulinemia,[47] insulin resistance[48] and hyperglycaemia.[49]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
