The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins.
Proto-TRK and proto-RET genes encode receptor type tyrosine kinases. Oncogenic rearrangements of both proto-oncogenes have been detected with a significant frequency in human papillary thyroid carcinomas. Chimeric Ret and Trk oncoproteins, encoded by different rearrangements of proto-TRK and proto-RET genes, display a constitutive phosphorylation on tyrosine. Moreover, it has been shown that phosphorylated tyrosine receptors, activated by their ligands, form multiprotein complexes responsible for transducing mitogenic or differentiation signals. We have therefore begun to analyse in this study the signal transduction pathways triggered by different Ret and Trk oncoproteins. We have shown that the SH2 domain of the adaptor protein Shc coimmunoprecipitates with all the Ret and Trk oncoproteins as well as with NGF-activated proto-Trk receptor. Tyrosine phosphorylation of Trk proteins both normal and oncogenic is necessary for their binding to Shc. In addition, in cells containing either Ret or Trk oncoproteins, Shc proteins are constitutively phosphorylated on tyrosine and bound to Grb2. Only in in vitro experiments were Ret and Trk oncoproteins shown to bind the SH2 region of Grb2. Finally, when proto-Trk product is stimulated by NGF, Shc phosphorylation and association with Grb2 are induced. In conclusion, we have shown that Ret and Trk oncoproteins can form multiprotein complexes, however, the functional meaning of the described interactions has to be elucidated.
Borrello
M G
MG
Divisione di Oncologia Sperimentale A, Istituto Nazionale Tumori, Milano, Italy.
Pelicci
G
G
Arighi
E
E
De Filippis
L
L
Greco
A
A
Bongarzone
I
I
Rizzetti
M
M
Pelicci
P G
PG
Pierotti
M A
MA
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic; D029721:Drosophila Proteins; D051380:GRB2 Adaptor Protein; D051379:Mice; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D029721:Drosophila Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C065400:oncogene protein trk; D014443:Tyrosine; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse