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The β-Catenin Axis Integrates Multiple Signals Downstream from RET/Papillary Thyroid Carcinoma Leading to Cell Proliferation

¹ Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Universita Federico II, Naples, Italy; ² Department of Genetics, Institute of Basic Molecular Sciences, University of Madras, Madras, India; ³ Division of Pathology, Department of Surgery, University of Pisa, Pisa, Italy; and ⁴ National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland

Requests for reprints: Massimo Santoro, Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano," Università Federico II di Napoli, via S. Pansini 5, 80131 Naples, Italy. Phone: 39-081-7463056; Fax: 39-081-7463037; E-mail: masantor{at}unina.it.

Key Words: thyroid cancer • tyrosine kinase • oncogene

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]

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