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. ß-catenin is usually involved in the maintenance of cell-to-cell adhesion and mediates the Wnt/ß-catenin pathway important during embryogenesis and in cellular malignant transformation. Recently, a novel mechanism of RET-mediated function through the ß-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/ß-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 ß-catenin cellular distribution as resulted in its co-immunoprecipitation with E-cadherin. We further investigated this hypothesis showing that TPC1 treated cells displayed predominantly ß-catenin cytosolic localization. Surprisingly, RET and ß-catenin co-immunoprecipitated in both ZD6474-treated and untreated TPC1 cells, suggesting that RET/ß-catenin interaction might not be affected by RET kinase inactivation. All together these results suggest that RET kinase activation is crucial for ß-catenin stabilization (pY654), localization and its signaling pathway activation but not for ß-catenin/RET physical interactions, in human papillary thyroid carcinomas. In conclusion, ZD6474, by inhibiting RET kinase, down-modulates ß-catenin pathway leading its recruitment to the membrane by E-cadherin.

Tartari, C., Donadoni, C., Manieri, E., Mologni, L., Mina, P., Villa, A., et al. (2011). Dissection of the RET/ß-catenin interaction in the TPC1 thyroid cancer cell line. AMERICAN JOURNAL OF CANCER RESEARCH, 1(6), 716-725.

Dissection of the RET/ß-catenin interaction in the TPC1 thyroid cancer cell line

TARTARI, CARMEN GIULIA;DONADONI, CARLA;MOLOGNI, LUCA;VILLA, ANTONELLO;GAMBACORTI PASSERINI, CARLO
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. ß-catenin is usually involved in the maintenance of cell-to-cell adhesion and mediates the Wnt/ß-catenin pathway important during embryogenesis and in cellular malignant transformation. Recently, a novel mechanism of RET-mediated function through the ß-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/ß-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 ß-catenin cellular distribution as resulted in its co-immunoprecipitation with E-cadherin. We further investigated this hypothesis showing that TPC1 treated cells displayed predominantly ß-catenin cytosolic localization. Surprisingly, RET and ß-catenin co-immunoprecipitated in both ZD6474-treated and untreated TPC1 cells, suggesting that RET/ß-catenin interaction might not be affected by RET kinase inactivation. All together these results suggest that RET kinase activation is crucial for ß-catenin stabilization (pY654), localization and its signaling pathway activation but not for ß-catenin/RET physical interactions, in human papillary thyroid carcinomas. In conclusion, ZD6474, by inhibiting RET kinase, down-modulates ß-catenin pathway leading its recruitment to the membrane by E-cadherin.
Articolo in rivista - Articolo scientifico
RET, ß-catenin, ZD6474, RET-inhibitor, protein interaction
English
716
725
Tartari, C., Donadoni, C., Manieri, E., Mologni, L., Mina, P., Villa, A., et al. (2011). Dissection of the RET/ß-catenin interaction in the TPC1 thyroid cancer cell line. AMERICAN JOURNAL OF CANCER RESEARCH, 1(6), 716-725.
Tartari, C; Donadoni, C; Manieri, E; Mologni, L; Mina, P; Villa, A; GAMBACORTI PASSERINI, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/28531
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