Creative Biostructure provides custom MemPro™ gene-to-structure services for insulin receptor.
The insulin receptor and the Insulin-like growth factor I receptor (IGF1R) are members of the tyrosine kinase class of membrane receptors, and are homologous to oncogenes of the tyrosine kinase class. The main physiological role of the insulin receptor appears to be metabolic regulation, whereas all other receptor tyrosine kinases are engaged in regulating cell growth and/or differentiation. Receptor tyrosine kinases are allosterically regulated by their cognate ligands and function as dimers. However, two closely related IGF1R and IGF2R have a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Additionally, all other EGF family member, these dimers are noncovalent, but insulin receptors are covalently maintained as functional dimers by disulfide bonds.
The insulin receptor exists in two splice variant isoforms; the ‘B’ isoform recognizes only insulin, but the ‘A’ isoform, which is the isoform that is most commonly expressed by tumors, recognizes both insulin and IGFII. The insulin receptor is a disulphide-linked (αβ)2 homodimer; the extracellular portion of each αβ protomer contains six domains. Insulin receptor and IGFR could form a “half” receptor and two half receptors could associate to form a homodimer or heterodimer. These heterodimerized receptor are called hybrid receptors and they show similar downstream signaling pathway.
Figure 1. Normal physiology of Insulin, insulin receptor and Insulin-like growth factor receptor
In contrast to epidermal growth factor and other tissue growth factors that are relevant to neoplastic disease, insulin functions as a classic hormone. Abnormal autocrine production of insulin by cancers is uncommon compared to ErbB2. Although many cancers display high rates of insulin-independent glucose uptake, there is evidence that, in some cases, tumour glucose uptake is also insulin-stimulated. The various anti-receptor antibodies that have been developed have many features in common, but they are not identical in terms of antibody subtype, half-life and so on. They all interfere with ligand binding to the IGF1R and also interfere with ligand binding to hybrid receptors, although this is less well documented. Despite the lack of interference with insulin binding, the use of these antibodies is associated with hyperglycaemia and hyperinsulinaemia, which can be severe, particularly if patients are also receiving steroids.
Patients with type 2 diabetes are supposed to have modestly increased cancer risk compared with normal individuals. This is due to the continuously expose to high levels of circulating insulin. Although, Insulin expression is confined to specialized pancreatic β-cells, and under normal circumstances it is tightly regulated by the level of circulating glucose. Insulin receptors are not confined to insulin-target tissues such as liver, muscle and fat, but extend to many other epithelial tissues. Certain synthetic insulin may be more dangerous than endogenous insulin, since it has distinct binding characters with insulin receptor and IGFR family.
Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update[J]. Nature Reviews Cancer, 2012, 12(3): 159-169.
Menting J G, Whittaker J, Margetts M B, et al. How insulin engages its primary binding site on the insulin receptor[J]. Nature, 2013, 493(7431): 241-245.