The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation.
The beta-catenin axis integrates multiple signals downstream from RET/papillary thyroid carcinoma leading to cell proliferation.
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DOI：
10.1158/0008-5472.can-08-1982
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Santoro M
中科院分区：
文献类型：
--
作者：
Castellone MD;De Falco V;Rao DM;Bellelli R;Muthu M;Basolo F;Fusco A;Gutkind JS;Santoro M
RET/PTC （RET/乳头状甲状腺癌）癌蛋白是由RET受体酪氨酸激酶结构域与外源基因编码的蛋白二聚化基元在框架内融合产生的。我们发现RET/PTC刺激β-catenin通路。RET/PTC通过刺激PI3K/AKT和Ras/ERK，促进GSK3β磷酸化，从而降低GSK3β介导的n端β-catenin （Ser33/Ser37/Thr41）磷酸化。此外，RET/PTC与β-catenin物理相互作用，增加其磷酸酪氨酸含量。增加的S/T（非磷酸化）/Y（磷酸化）β-catenin自由池由于Axin/GSK3β复合物结合亲和力降低而稳定，并激活T细胞因子/淋巴细胞增强因子（TCF/LEF）转录因子。此外，通过ERK通路，RET/PTC刺激camp响应元件结合蛋白（CREB）磷酸化，促进β-catenin-CREB-CBP/p300转录复合物的形成。含有β-catenin的转录复合物被募集到cyclin D1启动子上，并且在RET/PTC表达细胞中，cyclin D1基因启动子报告基因是活跃的。通过siRNA沉默β-catenin抑制RET/PTC转化的PC甲状腺细胞的增殖，而组成型活性β-catenin则刺激甲状腺细胞的自主增殖。因此，RET/PTC下游的多个信号事件汇聚到β-catenin上来刺激细胞增殖。
RET/PTC (RET/papillary thyroid carcinoma) 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 β-catenin pathway. By stimulating PI3K/AKT and Ras/ERK, RET/PTC promotes GSK3β phosphorylation, thereby reducing GSK3β-mediated N-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin, and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor. Moreover, through the ERK pathway, RET/PTC stimulates cAMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CBP/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC expressing cells. Silencing of β-catenin by siRNA inhibits proliferation of RET/PTC transformed PC thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation.