Insulin-like Growth Factor 1 Receptor

The Insulin-like growth factor (IGF) system comprises two main receptors, IGF-IR and IGF-IIR. Both IGF-IR and IGF-IIR are transmembrane glycoproteins that differ completely in their structure and function. IGF-IR is a tetramer of two equal α-subunits and two equal β-subunits. Structurally, IGF-IR resembles the insulin receptor with 60% homology. IGFs and insulin are proficient to cross-bind to each other's receptor, although with much weaker binding affinity than that for the preferred ligand. IGF-IR and insulin receptor (IR) can hybridize to form a heterodimer composed of one α-subunit and one β-subunit of each receptor. IGF-IIR (M6P receptor) is monomeric. In the extracellular domain of the receptor, three ligand-binding regions are found one for IGF-II binding and two for proteins containing mannose-6-phosphate (M6P) and the dormant form of transforming growth factor- (TGF-) β. IGF-IIR has high affinity for binding the IGF-II ligand but is a nonsignalling receptor. The IGFs are expressed ubiquitously and act in an autocrine/paracrine manner which including regulate cell proliferation, differentiation, apoptosis, and transformation through binding to the IGF-IR. Binding of IGF ligands to IGF-IR activates the receptor's tyrosine kinase activity, which triggers a cascade of reactions among a number of molecules involved in the signal transduction pathway, including the phosphatidyl-inositol-3 kinase (PI3K)-protein kinase B (Akt) pathway. IGF-IIR has no tyrosine kinase activity is considered to act like an antagonist to IGF-II, reducing its biologic activity by binding to IGF-II. Deregulation of IGF-IR signalling has been reported to contribute to a variety of diseases including diabetic retinopathy, diabetic nephropathy, age-related macular degeneration, cardiovascular disease, and aging and in a variety of cancers.