The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation.

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.Her e, we show that RET/PTC stimulates the B-catenin pathway.By stimulating PI3K/AKT and Ras/ extracellular signal-regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3B (GSK3B) phosphorylation, thereby reducing GSK3B-mediated NH2-terminal B-catenin (Ser33/Ser37/Thr41) phosphorylation.In addition, RET/PTC physically interacts with B-catenin and increases its phosphotyrosine content.The increased free pool of S/T(nonphospho)/ Y(phospho)B-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3B 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 B-catenin- CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing B-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC-expressing cells.Silencing of B-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC Cl3 thyrocytes, whereas a constitutively active form of B-catenin stimulates autonomous proliferation of thyroid cells.Thus, multiple signaling events downstream from RET/PTC converge on B-catenin to stimulate cell proliferation.