RET ALTERNATE SPLICING INFLUENCES THE INTERACTION OF ACTIVATED RET WITH THE SH2 AND PTB DOMAINS OF SHC, AND THE SH2 DOMAIN OF GRB2

Activating germline mutations of the RET receptor tyrosine kinase are found in the majority of cases of inherited cancer syndrome MEN 2, and inactivating mutations in some cases of dominantly inherited Hirschsp rung disease. Using RET activated by a MEN 2 mutation, we show that bo th the SH2 and PTB domains of the adaptor protein Shc interact with RE T, and we identify the PTB domain interaction site. Interaction with b oth the SH2 and PTB domains of She contributes to the transcriptional activation of a serum response element. RET alternate splicing affects the strength of interaction with both the She SH2 and PTB domains. In addition, a splice isoform-specific HSCR missense mutation, which doe s not inactivate the RET kinase activity, decreases the strength of th e PTB domain interaction and the level of RET-dependent She phosphoryl ation.