DISTINCT BIOLOGICAL PROPERTIES OF 2 RET ISOFORMS ACTIVATED BY MEN 2A AND MEN 2B MUTATIONS

Germline mutations of the RET proto-oncogene, which codes for a recept or tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A ) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. Th e RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634-->Arg) and t he unique MEN 2B mutation (Met918-->Thr) in two RET isoforms of 1114 a nd 1072 amino acids which differ in the carboxy-terminus part, Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutatio n was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimu lated the most prominent neurite outgrowth in PC12 cells, while the sh ort RET isoform counterpart elicited a very weak differentiation effec t in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins inv olved the engagement of a Ras-dependent pathway. These findings provid e evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activa ting MEN 2 mutation.