Interrelationships among receptor structures for insulin and peptide growth factors

Abstract

The development and application of affinity cross-linking methodology have allowed the identification of receptor subunits for at least seven different polypeptide growth factors. In the case of insulin, a complex disulfide-linked receptor structure has been deduced by this method in conjunction with results obtained from affinity purification of the receptor complex. The minimum subunit structure deduced for this receptor is (beta-S-S-alpha)-S-S-(alpha-S-S-beta), where alpha is a 125,000-dalton glycoprotein subunit and beta is a 90,000-dalton glycoprotein subunit. A receptor species with high affinity for insulinlike growth factor (IGF) I and low affinity for insulin exhibits striking homology to this insulin receptor structure. A third receptor structure has high affinity for IGF-II and lower affinity for IGF-I, with essentially no affinity for insulin. This IGF-II receptor structure has a molecular weight of about 250,000 and shows no evidence of disulfide linkage to other subunits. Receptor polypeptides with high affinity for epidermal growth factor, nerve growth factor, transformation growth factor, or platelet-derived growth factor have been linked to the respective 125I-labeled ligands and exhibit molecular weights of about 160,000, 140,000, 60,000, and 170,000, respectively. None of these receptors appears to be disulfide linked to other subunits. No apparent structural homology among these receptor types has been detected as yet. Recent evidence suggests that there may be important biochemical linkages between certain of the receptor systems. For example, an effect of insulin mediated through its own receptor in intact adipocytes or H-35 hepatoma cells rapidly results in a 5- to 10-fold increase in the affinity of the 250,000-dalton IGF-II receptor for 125I-labeled IGF-II. This may reflect an important mechanism by which insulin can simultaneously mediate rapid effects on cellular enzymes through its own receptor and indirectly promote cellular growth by potentiating growth factor action through this activation of the IGF-II receptor.