A novel RET kinase-β-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma

Taranjit S. Gujral, Wendy Van Veelen, Douglas S. Richardson, Shirley M. Myers, Jalna A. Meens, Dennis S. Acton, Mireia Duñach, Bruce E. Elliott, Jo W.M. Höppener, Lois M. Mulligan

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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 β-catenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the β-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, β-catenin and show that the interaction between RET and β-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, β-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 β-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of β-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a β-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma. ©2008 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)1338-1346
JournalCancer Research
Volume68
DOIs
Publication statusPublished - 1 Mar 2008

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    Gujral, T. S., Van Veelen, W., Richardson, D. S., Myers, S. M., Meens, J. A., Acton, D. S., Duñach, M., Elliott, B. E., Höppener, J. W. M., & Mulligan, L. M. (2008). A novel RET kinase-β-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma. Cancer Research, 68, 1338-1346. https://doi.org/10.1158/0008-5472.CAN-07-6052