THE ONCOGENIC VERSIONS OF THE RET AND TRK TYROSINE KINASES BIND SHC AND GRB2 ADAPTER PROTEINS

Proto-TRK and proto-RET genes encode receptor type tyrosine kinases. O ncogenic rearrangements of both proto-oncogenes have been detected wit h a significant frequency in human papillary thyroid carcinomas. Chime ric Ret and Trk oncoproteins, encoded by different rearrangements of p roto-TRK and proto-RET genes, display a constitutive phosphorylation o n tyrosine. Moreover, it has been shown that phosphorylated tyrosine r eceptors, activated by their ligands, form multiprotein complexes resp onsible for transducing mitogenic or differentiation signals. We have therefore begun to analyse in this study the signal transduction pathw ays triggered by different Ret and Trk oncoproteins. We have shown tha t the SH2 domain of the adaptor protein She coimmunoprecipitates with all the Ret and Trk oncoproteins as well as with NGF-activated proto-T rk receptor. Tyrosine phosphorylation of Trk proteins both normal and oncogenic is necessary for their binding to She. In addition, in cells containing either Ret or TrK oncoproteins, She proteins are constitut ively phosphorylated on tyrosine and bound to Grb2. Only in in vitro e xperiments were Ret and Trk oncoproteins shown to bind the SH2 region of Grb2. Finally, when proto-Trk product is stimulated by NGF, She pho sphorylation and association with Grb2 are induced. In conclusion, we have shown that Ret and Trk oncoproteins can form multiprotein complex es, however, the functional meaning of the described interactions has to be elucidated.