Insulin-like growth factor I signalling through heterodimers of insulin and insulin-like growth factor I receptors.
OBJECTIVE
To clarify the specific signalling pathway of IGF-I, we studied the functional role of heterodimers composed of IGF-I receptor and insulin receptor for the IGF-I signalling.


METHODS
Either wild type or truncated insulin receptor lacking 365 amino acids from the carboxyl-terminus, were overexpressed in the Rat-1 fibroblasts. Heterodimers between rat IGF-I receptor and exogenous insulin receptors were identified by a human specific anti-insulin receptor monoclonal antibody after ligand affinity-labeling. IGF-I-stimulated auto-phosphorylation of the receptors, mitogenesis and AIB uptake were compared among the Rat-1 cells, Rat-1 cells overexpressing wild type insulin receptors and truncated insulin receptors.


RESULTS
Thirty to sixty percent of IGF-I receptors were found to form heterodimer complex with either wild type insulin receptors or truncated insulin receptors. Although heterodimers with the truncated receptors were not autophosphorylated in response to IGF-I in vitro, in vivo autophosphorylation of IGF-I receptors occurred in these three cell lines. The dose response curves of IGF-I stimulated DNA synthesis were comparable among the three cell lines. The responsiveness to IGF-I stimulation was increased for mitogenesis in the cells with heterodimers, but was comparable in the AIB uptake study.


CONCLUSIONS
These results indicated that the heterodimer receptors, even with the kinase-defective insulin receptors, retained functional activities for the IGF-I-stimulated mitogenic signaling.
Takata
Y
Y
First Department of Medicine, Toyama Medical and Pharmaceutical University, Japan.
Kobayashi
M
M
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003432:Cross-Linking Reagents; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007700:Kinetics; D046911:Macromolecular Substances; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D055503:Protein Multimerization; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013936:Thymidine / Q000378:metabolism; D014162:Transfection
D000621:Aminoisobutyric Acids; D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D046911:Macromolecular Substances; C100049:2-aminoisobutyric acid; D007334:Insulin-Like Growth Factor I; D004247:DNA; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D013936:Thymidine