A FUNCTIONAL ASSESSMENT OF INSULIN INSULIN-LIKE GROWTH-FACTOR-I HYBRID RECEPTORS

Insulin/insulin-like growth factor-I (IGF-I) hybrid receptors are comp osed of an ap-heterodimer from an insulin receptor and an alpha beta h eterodimer from an IGF-I receptor. In this study, we evaluate the effe ct of insulin receptor overexpression on hybrid formation. The more hu man insulin receptors expressed in rodent fibroblasts, the greater the percentage of endogenous rat IGF-I receptors that form hybrid recepto rs. The IGF-I receptor in rodent fibroblasts has two receptor isoforms , one with a 95-kilodalton (kDa) beta-subunit and one with an 105 kDa beta-subunit. A truncated mutant insulin receptor was used to demonstr ate that only activated IGF-I receptors with the 105-kDa beta-subunit form hybrid receptors with the insulin receptor. Insulin/IGF-I hybrid receptors with a kinase-defective insulin heterodimer undergo trans an d a small amount of cis autophosphorylation, but overall autophosphory lation is markedly decreased from that seen in hybrids with a kinase-c ompetent insulin receptor. The kinase-defective insulin receptor heter odimer functions as a dominant-negative, inhibiting phosphorylation by the kinase-competent IGF-I receptor heterodimer. The kinase-defective hybrid receptors are, however, able to undergo internalization. Despi te an increasing percentage of insulin/IGF-I hybrid receptors in the t hree cell lines studied, the rates of IGF-I internalization and degrad ation remain similar to those mediated by the IGF-I receptor and disti nct from those of insulin receptor heterotetramers. In conclusion, IGF -I-stimulated insulin/IGF-I hybrid receptors function like IGF-I recep tors, rather than like insulin receptors.