ONCOGENIC RET RECEPTORS DISPLAY DIFFERENT AUTOPHOSPHORYLATION SITES AND SUBSTRATE-BINDING SPECIFICITIES

The c-ret proto-oncogene encodes a receptor tyrosine kinase which play s an important role in neural crest as well as kidney development, Gen etic studies have demonstrated that germ line mutations in the ret onc ogene are the direct cause of multiple endocrine neoplasia (MEN) 2A an d 2B, familial medullary thyroid carcinoma (FMTC), and Hirschsprung's disease. However, despite the large body of genetic and biological evi dence suggesting the importance of RET in development and neoplastic p rocesses, the signal transduction mechanisms of RET remain unknown. To begin to understand the molecular mechanisms of the disease states ca used by mutations in RET, the patterns of autophosphorylation of the w ild-type RET and the MEN mutants were studied using site-directed muta genesis and phosphopeptide mapping, Among the 6 autophosphorylation si tes found in the wild-type RET receptor, the MEN2B mutant lacked phosp horylation at Tyr-1096, leading to decreased Grb2 binding, while simul taneously creating a new phosphorylation site. These changes in autoph osphorylation suggest that the MEN2B mutation may result in the more a ggressive MEN2B phenotype by altering the receptor's signaling capabil ities.