The roles of phosphotyrosines-294, -404, and -451 in RET/PTC1-induced thyroid tumor formation.
RET/PTC1 is a rearranged form of the RET proto-oncogene detected in human papillary thyroid carcinomas. We previously showed that thyroid-targeted expression of RET/PTC1 leads to thyroid tumor formation in Tg-PTC1 transgenic mice. Signal transduction pathways mediated by phosphotyrosine 294, 404, or 451 in RET/PTC1 have been shown to be critical for RET-induced transforming activity in vitro. To investigate the contribution of these signaling pathways in RET/PTC1-induced thyroid tumor formation in vivo, we generated and characterized transgenic mice expressing thyroid-targeted RET/PTC1 mutants carrying a site-directed mutation changing tyrosine (Y) to phenylalanine (F) at the residue 294, 404, or 451. In contrast to the 100% tumor formation rate in Tg-PTC1 transgenic mice, tumor formation rates were significantly decreased in Tg-PTC1-Y294F (6%), Tg-PTC1-Y404F (41%), and Tg-PTC1-Y451F (30%) transgenic mice. This indicates that signaling pathways mediated by pY294, pY404, and pY451 do play a role in RET/PTC1-induced tumor formation. However, as tumors are still able to form in some mice within these three mutant transgenic groups, it indicates that none of the signaling pathways mediated by pY294, pY404, or pY451, are solely essential for RET/PTC1-induced tumor formation.
Buckwalter
Tara L F
TL
Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, OH 43210, USA.
Venkateswaran
Anjli
A
Lavender
Marc
M
La Perle
Krista M D
KM
Cho
Je-Yoel
JY
Robinson
Michael L
ML
Jhiang
Sissy M
SM
D019943:Amino Acid Substitution; D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity; D002291:Carcinoma, Papillary / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004032:Diet / Q000009:adverse effects; D006801:Humans; D007455:Iodine / Q000172:deficiency; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000502:physiology*; D011441:Propylthiouracil / Q000633:toxicity; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000235:genetics*; D014404:Tubulin / Q000096:biosynthesis / Q000235:genetics
D013956:Antithyroid Agents; C000715470:MAS1 protein, human; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D014404:Tubulin; D019000:Phosphotyrosine; D011441:Propylthiouracil; D007455:Iodine; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human