title: A novel RET kinase-beta-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma.
abstract: The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of beta-catenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the beta-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, beta-catenin and show that the interaction between RET and beta-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, beta-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate beta-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a beta-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.
authors.affiliation: Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
authors.forename: Taranjit S
authors.initials: TS
authors.lastname: Gujral
authors.forename: Wendy
authors.initials: W
authors.lastname: van Veelen
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Richardson
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Myers
authors.forename: Jalna A
authors.initials: JA
authors.lastname: Meens
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Acton
authors.forename: Mireia
authors.initials: M
authors.lastname: Duñach
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Elliott
authors.forename: Jo W M
authors.initials: JW
authors.lastname: Höppener
authors.forename: Lois M
authors.initials: LM
authors.lastname: Mulligan
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015398:Signal Transduction; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D051096:Proto-Oncogene Proteins c-ret