The β-Catenin Axis Integrates Multiple Signals Downstream from RET/Papillary Thyroid Carcinoma Leading to Cell Proliferation
- 1 March 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (5), 1867-1876
- https://doi.org/10.1158/0008-5472.can-08-1982
Abstract
RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the β-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal–regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3β (GSK3β) phosphorylation, thereby reducing GSK3β-mediated NH2-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP–responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC–expressing cells. Silencing of β-catenin by small interfering RNA inhibits proliferation of RET/PTC–transformed PC Cl3 thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation. [Cancer Res 2009;69(5):1867–76]This publication has 49 references indexed in Scilit:
- Deoxyribonucleic Acid Profiling Analysis of 40 Human Thyroid Cancer Cell Lines Reveals Cross-Contamination Resulting in Cell Line Redundancy and MisidentificationJournal of Clinical Endocrinology & Metabolism, 2008
- A Novel RET Kinase–β-Catenin Signaling Pathway Contributes to Tumorigenesis in Thyroid CarcinomaCancer Research, 2008
- Bcr-Abl stabilizes β-catenin in chronic myeloid leukemia through its tyrosine phosphorylationThe EMBO Journal, 2007
- Erk Associates with and Primes GSK-3β for Its Inactivation Resulting in Upregulation of β-CateninMolecular Cell, 2005
- Reduced E-cadherin expression contributes to the loss of p27 kip1 -mediated mechanism of contact inhibition in thyroid anaplastic carcinomasCarcinogenesis: Integrative Cancer Research, 2005
- Docking Protein FRS2 Links the Protein Tyrosine Kinase RET and Its Oncogenic Forms with the Mitogen-Activated Protein Kinase Signaling CascadeMolecular and Cellular Biology, 2001
- Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activationOncogene, 2001
- Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factorOncogene, 2000
- The ret/ptc1 Oncogene Is Activated in Familial Adenomatous Polyposis-Associated Thyroid Papillary CarcinomasJournal of Clinical Endocrinology & Metabolism, 1998
- c-erbB-2 Gene Product Directly Associates with β-Catenin and PlakoglobinBiochemical and Biophysical Research Communications, 1995