ROLE OF THE CARBOXYL-TERMINAL DOMAINS OF THE INSULIN AND INSULIN-LIKEGROWTH-FACTOR-I RECEPTORS IN RECEPTOR FUNCTION

The insulin and insulin-like growth factor I receptors (IR and IGF-IR, respectively) are heterotetrameric tyrosine kinases consisting of two extracellular ligand-binding alpha subunits and two transmembrane cat alytic beta subunits. A number of lines of evidence have suggested tha t the IR and IGF-IR differ with respect to their ability to elicit mit ogenic versus metabolic events upon activation by cognate ligands. To ascertain the contribution of the poorly conserved carboxyl-terminal d omains to the differential functioning of the IR and IGF-IR, we have c onstructed receptor chimeras in which the carboxyl-terminal domain of one receptor was fused to the remainder of the heterologous receptor. The responses of a number of parameters after ligand stimulation were examined in stably transfected NIH-3T3 cells expressing the chimeric r eceptors or the analogous wild-type receptor sequence. Replacement of the IR carboxyl terminus with that of the IGF-IR severely affected ins ulin stimulated responses, whereas substitution of the carboxyl termin us of the IGF-IR with that of the IR had a minimal effect. These data suggest that the carboxyl-terminal domains of the IR and IGF-IR are no t interchangeable and that the mitogenic activity of the IR can be inf luenced by sequences present in the carboxyl-terminal domain. The anal ogous functions of the IGF-IR, on the other hand, do not appear to be greatly affected by the presence of the IR carboxyl-terminal domain.