Figure 4. RET signaling pathways.

domains. In contrast, the binding to Tyr1062 of ENIGMA, a PDZ-LIM protein, is phospho-independent. Furthermore, ENIGMA binds specifically RET9, since short isoform-specific aminoacid residues +2 to +4 to Tyr1062 are required for interaction with ENIGMA (Borrello, M. G. et al., 2002).

Tyr1062-associated adaptor proteins contribute to activation of several downstream signaling pathways such as the RAS/ERK, PI3K/AKT, p38MAPK, JNK and ERK5 (Besset, V.et al., 2000; Hayashi, H. et al., 2000; Hayashi, Y. et al., 2001; Segouffin-Cariou, C. et al., 2000; Kurokawa, K. et al., 2003).

Tyr1096 is the most C-terminal phosphorylated tyrosine residue and it is unique to the long isoform (Liu, X. et al., 1996). The Tyr1062 multidocking site, although common to both isoforms, is only two residues amino-terminal to the C-terminal RET splice site, which alters the context of this residue between RET9 and RET51. Accordingly, Tyr1062 in short and long isoform does appear to have differential interactions with SHC and ENIGMA proteins (Lorenzo, M. J. et al., 1997; Borrello, M. G. et al., 2002). In addition, the two isoforms, though sharing identical extracellular domains, do not associate with each other and show different tyrosine phosphorylated associated proteins in sympathetic neurons (Tsui-Pierchala, B. A. et al., 2002).

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