Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc.
The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity.
Roccato
E
E
Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy.
Miranda
C
C
Ranzi
V
V
Gishizki
M
M
Pierotti
M A
MA
Greco
A
A
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D053938:DNA Fragmentation; D005799:Genes, Dominant; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009154:Mutation; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011233:Precipitin Tests; D011506:Proteins / Q000378:metabolism*; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013961:Thyroid Gland / Q000378:metabolism; D014178:Translocation, Genetic; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C065400:oncogene protein trk; D014443:Tyrosine; D008156:Luciferases; D020917:Receptor, trkA