EXPRESSION OF A KINASE-DEFICIENT IGF-I-R SUPPRESSES TUMORIGENICITY OFRHABDOMYOSARCOMA CELLS CONSTITUTIVELY EXPRESSING A WILD-TYPE IGF-I-R

Previous results have shown that the insulin-like growth factor type I receptor (IGF-I-R) plays a critical role in the control of rhabdomyos arcoma (RMS) growth. The purpose of this study was to investigate whet her a mutated IGF-I-R, when expressed in RMS cells, may interfere with the function of the endogenous wild-type IGF-I-R. We also examined wh ether the expression of a mutated IGF-I-R may induce phenotypic change s in RMS cells. We used here the mutated IGF-I-R with a lysine to argi nine residue 1003 substitution, called IGF-I-KR, which carries a mutat ion in the ATP-binding domain of the intracellular beta subunit, while the extracellular, ligand binding alpha subunit remains unchanged. We observed that the expression of this mutated IGF-I-KR markedly decrea sed the response of RMS cells to stimulation with IGF-I. White stimula tion with IGF-I increases the autophosphorylation of IGF-I-R in the pa rent cells, stimulation with IGF-I failed to produce a comparable incr ease in autophosphorylation in the cells expressing the mutated IGF-I- KR. We also observed a decreased plating efficiency of cells expressin g the mutated IGF-I-KR. Consistently, a decrease of RMS growth in vivo was observed in an animal model. Our data suggest that the IGF/IGF-I- R signaling pathway may be inhibited by expressing a mutated ICF-I-KR and that such a mutant gene could be utilized in developing novel ther apeutic strategies to suppress RMS growth. (C) 1998 Wiley-Liss, Inc.da gger