Insulin-like growth factor I signalling through heterodimers of insulin and insulin-like growth factor I receptors.

PURPOSE

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.