IDENTIFICATION OF DOMAINS OF THE INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR THAT ARE REQUIRED FOR PROTECTION FROM APOPTOSIS

Using a series of insulin-like growth factor I (IGF-I) receptor mutant s, we have attempted to define domains required for transmitting the a ntiapoptotic signal from the receptor and to compare these domains wit h those required for mitogenesis or transformation. In FL5.12 cells tr ansfected with wild-type IGF-I receptors, IGF-I affords protection fro m interleukin 3 withdrawal but is not mitogenic. An IGF-I receptor lac king a functional ATP binding site provided no protection from apoptos is. However, receptors mutated at tyrosine residue 950 or in the tyros ine cluster (1131, 1135, and 1136) within the kinase domain remained c apable of suppressing apoptosis, although such mutations are known to inactivate transforming and mitogenic functions. In the C terminus of the IGF-I receptor, two mutations, one at tyrosine 1251 and one which replaced residues histidine 1293 and lysine 1294, abolished the antiap optotic function, whereas mutation of the four serines at 1280 to 1283 did not. Interestingly, receptors truncated at the C terminus had enh anced antiapoptotic function. In Rat-1/ c-MycER fibroblasts, the Y950F mutant and the tyrosine cluster mutant could still provide protection from c-Myc-induced apoptosis, whereas mutant Y1250/1251F could not. T hese studies demonstrate that the domains of the IGF-I receptor requir ed for its antiapoptotic function are distinct from those required for its proliferation or transformation functions and suggest that domain s of the receptor required for inhibition of apoptosis are necessary b ut not sufficient for transformation.