How distinct are the insulin and insulin-like growth factor I signalling systems?
Insulin and insulin-like growth factor I (IGF-I) are closely related peptides. Insulin is primarily involved in regulating carbohydrate, fat and protein metabolism. IGF-I, however, regulates growth and development of the whole organism as well as differentiated functions in specific tissues. Each of these functions are mediated by specific tyrosine kinase receptors expressed on the cell surface. The insulin and IGF-I receptors, though separate gene products, are very similar. Amino acid similarities range between 40 and 85% in different domains, the highest degree of homology being found in the tyrosine kinase domain. Tertiary structure similarities further explain the interactions of each ligand with the heterologous receptor; thus insulin receptors bind insulin with high affinity and IGF-I with lower affinity, and the opposite is true for the IGF-I receptor. Since each ligand can stimulate both receptors and both receptors seem capable of mediating both metabolic and growth activities, what separates these two distinct physiological roles? The interaction of the ligands with their own specific high affinity receptors is facilitated by the presence of IGF-specific binding proteins (BPs) which, however, do not bind insulin. These BPs, found both in the circulation and in tissues, bind all the circulating IGFs and transport the IGFs to their target tissues, thus ensuring that at physiological concentrations IGF-I will only interact with its own receptor. Furthermore, they modulate IGF effects. Since insulin circulates at much lower concentrations compared with the IGFs, this ensures that insulin will only interact with high-affinity insulin receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Adamo
M
M
Diabetes Branch, National Institutes of Health, Bethesda, MD 20892.
Roberts
C T
CT
LeRoith
D
D
D000818:Animals; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D011485:Protein Binding; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011972:Receptor, Insulin