Signal transduction elements of TC21, an oncogenic member of the R-Ras subfamily of GTP-binding proteins.
TC21 is a Ras-like GTPase with high oncogenic potential that is found mutated in some human tumors and overexpressed in breast cancer cell lines. We have conducted cellular and biochemical studies in order to understand the role of this protein in signal transduction and to unveil the signaling elements that participate in the TC21 pathway. Using gene transfer experiments, we demonstrate here that the TC21 oncogene can induce both cellular transformation in mouse fibroblasts and neuronal-like differentiation in rat PC12 cells. Interestingly, the proto-oncogenic version of TC21 shows also a lower, but significant, activity in both biological processes. We also demonstrate that the similarity of the cellular responses induced by TC21 and Ras derive from the utilization of overlapping pathways. Thus, the exchange of guanosine nucleotides in wild type TC21 is catalyzed by Ras exchange factors. Moreover, TC21 binds physically to c-Raf-1 in a GTP-dependent manner. Finally, overexpression of TC21G23V in NIH3T3 cells results in the activation of c-Raf-1 and the MAPK and the JNK branches of serine/threonine cascades. From these results, we conclude that TC21 promotes Ras-like responses in diverse cell types due to the use of overlapping, if not identical, signaling elements of the Ras oncogenic pathway.
Movilla
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Department of Pathology, State University of New York at Stony Brook, University Hospital, Level 2, Room 718-B, Stony Brook, New York, NY 11794-7025, USA.
Crespo
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Bustelo
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D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020663:ras Guanine Nucleotide Exchange Factors / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D015513:Oncogene Proteins; D011993:Recombinant Fusion Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C085929:RRAS protein, human; C513254:Rras protein, mouse; D018631:ras Proteins; D020741:rho GTP-Binding Proteins