Signal transduction by a chimeric insulin-like growth factor-1 (IGF-1) receptor having the carboxyl-terminal domain of the insulin receptor.

Insulin-like growth factor-1 receptors (IGF-1R) and insulin receptors (IR) are closely related tyrosine kinases. However, the IR plays a major role in metabolism control, whereas the IGF-1R is mainly involved in growth and differentiation. With these observations in mind, we wished to define the regions of IR and IGF-1R responsible for generation of biological specificity. We constructed a chimeric IGF-1R in which the carboxyl-terminal domain was replaced by that of IR. This receptor (IGF/CTIR) was expressed in NIH3T3 cells, and we compared its biological activity with that of wild-type receptors. The IGF/CTIR was fully functional regarding kinase activity and biological properties. Comparison of insulin and IGF-1 effects on IR and IGF-1R cells, respectively, indicated that the IR is more efficient in stimulating glycogen synthesis and p44mapk activity than is the IGF-1R. Interestingly, in IGF/CTIR16 cells expressing only 250,000 receptors glycogen synthesis was better stimulated than in IGF-1R cells with 600,000 receptors. Similarly, p44mapk activation was slightly higher in IGF/CTIR16 cells than in IGF-1R cells. These results suggest that the carboxyl-terminal domain of IR is more tightly coupled to the stimulation of glycogen synthesis and to the p44mapk pathway than is that of IGF-1R. We propose that this domain plays a crucial role in the transmission of biological effects and could account, at least in part, for receptor specificity.