Am J Cancer Res 2011;1(6):716-715

Original Article
Dissection of the RET/β-catenin interaction in the TPC1 thyroid cancer cell line

Carmen J Tartari, Carla Donadoni, Elisa Manieri, Luca Mologni, Pamela Della Mina, Antonello Villa, Carlo Gambacorti-Passerini

Department of Clinical Medicine, Via Cadore 48, University of Milano-Bicocca, Monza, 20052, Italy; Hemostasis and Thrombosis
Center & Division of Immunohematology and Transfusion Medicine, Ospedali Riuniti, Bergamo, 24128, Italy; Department
Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III, C/ Melchor Fernández
Almagro, 3 28029 Madrid Spain; Consorzio MIA University of Milano-Bicocca, Monza, 20052, Italy; Unit of Immunotherapy of
Human Tumors, Fondazione IRCCS, Milan, Italy.

Received May 9, 2011; accepted May 27, 2011; Epub June 1, 2011; Published June 30, 2011

Abstract: The RET receptor tyrosine kinase is a member of the cadherin superfamily and plays a pivotal role in cell survival,
differentiation and proliferation. Currently, 12 ret/ptc chimeric oncogenes, characterized by the fusion between the intracellular
domain of RET and different activating genes, which can cause ligand-independent dimerization and constitutive activation, have
been described. β-catenin is usually involved in the maintenance of cell-to-cell adhesion and mediates the Wnt/β-catenin
pathway important during embryogenesis and in cellular malignant transformation. Recently, a novel mechanism of RET-
mediated function through the β-catenin pathway has been reported in multiple endocrine neoplasia type 2 and in sporadic
thyroid carcinomas. Here, we investigated the effects of the ZD6474, a small molecule RET-inhibitor, on RET/β-catenin
interaction. We confirmed the ZD6474 mediated-inhibition of recombinant RET kinase and of growth of cells expressing
RET/PTC. Interestingly, we firstly observed reduced cellular mobility and changed morphology of TPC1 treated cells suggesting
that RET-inhibitor could affect β-catenin cellular distribution as resulted in its co-immunoprecipitation with E-cadherin. We further
investigated this hypothesis showing that TPC1 treated cells displayed predominantly β-catenin cytosolic localization.
Surprisingly, RET and β-catenin co-immunoprecipitated in both ZD6474-treated and untreated TPC1 cells, suggesting that
RET/β-catenin interaction might not be affected by RET kinase inactivation. All together these results suggest that RET kinase
activation is crucial for β-catenin stabilization (pY654), localization and its signaling pathway activation but not for β-catenin/RET
physical interactions, in human papillary thyroid carcinomas. In conclusion, ZD6474, by inhibiting RET kinase, down-modulates
β-catenin pathway leading its recruitment to the membrane by E-cadherin. (AJCR0000067).

Keywords: RET, β-catenin, ZD6474, RET-inhibitor, protein interaction

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Address all correspondence to:
Dr. Carlo Gambacorti-Passerini
Dept. of Clinical Medicine, Via Cadore 48
University of Milano-Bicocca
Monza, 20052, Italy.
E-mail:
carlo.gambacorti@unimib.it
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American Journal of Cancer Research
ISSN: 2156-6976