A functional assessment of insulin/insulin-like growth factor-I hybrid receptors.
Insulin/insulin-like growth factor-I (IGF-I) hybrid receptors are composed of an alpha beta-heterodimer from an insulin receptor and an alpha beta-heterodimer from an IGF-I receptor. In this study, we evaluate the effect of insulin receptor overexpression on hybrid formation. The more human insulin receptors expressed in rodent fibroblasts, the greater the percentage of endogenous rat IGF-I receptors that form hybrid receptors. 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 demonstrate 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 and a small amount of cis autophosphorylation, but overall autophosphorylation is markedly decreased from that seen in hybrids with a kinase-competent insulin receptor. The kinase-defective insulin receptor heterodimer 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. Despite an increasing percentage of insulin/IGF-I hybrid receptors in the three cell lines studied, the rates of IGF-I internalization and degradation remain similar to those mediated by the IGF-I receptor and distinct from those of insulin receptor heterotetramers. In conclusion, IGF-I-stimulated insulin/IGF-I hybrid receptors function like IGF-I receptors, rather than like insulin receptors.
Seely
B L
BL
Department of Medicine, University of California-San Diego, La Jolla 92093.
Reichart
D R
DR
Takata
Y
Y
Yip
C
C
Olefsky
J M
JM
D000818:Animals; D001667:Binding, Competitive; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007163:Immunosorbent Techniques; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007700:Kinetics; D046911:Macromolecular Substances; D010766:Phosphorylation; D055503:Protein Multimerization; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011972:Receptor, Insulin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D007328:Insulin; D046911:Macromolecular Substances; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin