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. Here, we show that RET/PTC stimulates the beta-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal-regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3beta (GSK3beta) phosphorylation, thereby reducing GSK3beta-mediated NH(2)-terminal beta-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with beta-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)beta-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3beta 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 beta-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing beta-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC-expressing cells. Silencing of beta-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC Cl3 thyrocytes, whereas a constitutively active form of beta-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on beta-catenin to stimulate cell proliferation.
Castellone
Maria Domenica
MD
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.
De Falco
Valentina
V
Rao
Deva Magendra
DM
Bellelli
Roberto
R
Muthu
Magesh
M
Basolo
Fulvio
F
Fusco
Alfredo
A
Gutkind
J Silvio
JS
Santoro
Massimo
M
D002291:Carcinoma, Papillary / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019000:Phosphotyrosine / Q000032:analysis; D011401:Promoter Regions, Genetic; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000502:physiology; D013964:Thyroid Neoplasms / Q000473:pathology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000502:physiology*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051820:TCF Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; D019000:Phosphotyrosine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3