The β-Catenin axis integrates multiple signals downstream from RET/Papillary thyroid carcinoma leading to cell proliferation

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/FTC stimulates the-catenin pathway. By stimulating PI3K/AKT and Ras/ extracellular signal-regulated kinase (ERK), RET/PTC pro-motes glycogen synthase kinase 3 (GSK3) phosphorylation, thereby reducing GSK3(3-mediated NH2-terminal-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with-catenin and increases its phospho-tyrosine content. The increased free pool of S/T(nonphospho)/ Y(phospho)-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3 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-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing-catenin are recruited to the cyclin Dl promoter and a cyclin Dl gene promoter reporter is active in RET/PTC-expressing cells. Silencing of-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC C13 thyrocytes, whereas a constitu-tively active form of-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on-catenin to stimu-late cell proliferation.