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— in RET C-terminus

Impairment of binding of docking proteins

RET gene was identified in 1985 as a novel oncogene, following transfection of NIH3T3 cells with DNA from a human T-cell lymphoma (Takahashi, M. et al., 1985). The transforming gene resulted from a recombination event between two unlinked DNA sequences, which occurred during the transfection process; hence the name RET, for 'rearranged during transfection'. The resulting chimaeric gene encoded a fusion protein comprising an amino-terminal region that displayed a putative zinc finger motif fused to a tyrosine kinase domain. Subsequently, the name RET has been retained to designate the gene coding for the tyrosine kinase protein of the fused oncogene. Rearrangements of RET with different genes are found frequently in papillary thyroid carcinomas (RET/PTCs) (Grieco, M. et al., 1990; Santoro, M. et al., 1992). On the other hand gain-of-function mutations of RET cause sporadic thyroid and adrenal cancers (Lindor, N. M. et al., 1994; Beldjord, C. et al., 1995; Komminoth, P. et al., 1996) as well as cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN2A and MEN2B) and familial medullary thyroid carcinoma (FMTC) (reviewed in Mulligan, L. M. et al., 1995a; Goodfellow, P. J. et al., 1995; Pasini, B. et al., 1996). Interestingly, loss-of-function mutations of the same RET gene cause Hirschsprung's disease (HSCR) or colonic aganglionosis (reviewed in Amiel, J. et al., 2001) (Table 1).

RET encodes a transmembrane tyrosine kinase displaying a structure similar to that of other receptor tyrosine kinases (RTKs), comprising extracellular, transmembrane and cytoplasmic domains.

The large extracellular portion, preceded by a typical cleavable signal sequence of 28 aminoacids, has no similarity with other RTKs and contains a conserved cysteine-rich region close to the cellular membrane and a more distal region with homology to the cadherin family of cell adhesion molecules (Takahashi, M. et al., 1988; Schneider, R., 1992; Iwamoto, T. et al., 1993; Takahashi, M. et al., 1989). Cadherins are cell—cell adhesion proteins and their adhesive properties depend on a domain of about 110 amino acids tandemly repeated in the extracellular region. RET

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