Transforming growth factor-β (TGF-β) is major inducer of epithelial-to-mesenchymal transition (EMT), which associates with cancer cell metastasis and resistance to chemotherapy and targeted drugs, through both transcriptional and non-transcriptional mechanisms. We previously reported that, in cancer cells, heightened mitogenic signaling allows TGF-β-activated Smad3 to interact with poly(RC) binding protein 1 (PCBP1) and together they regulate many alternative splicing events that favors expression of protein isoforms essential for EMT, cytoskeletal rearrangement, and adherens junction signaling. Here we show that the exclusion of TGF-β-activated kinase 1 (TAK1) variable exon 12 requires another RNA-binding protein, Fox-1 homolog 2 (Rbfox2), which binds intronic sequences in front of exon 12 independently of the Smad3-PCBP1 complex. Functionally, exon 12-excluded TAK1∆E12 and full-length TAK1FL are distinct. The short isoform TAK1∆E12 is constitutively active and supports TGF-β-induced EMT and nuclear factor kappa B (NF-κB) signaling, whereas the full-length isoform TAK1FL promotes TGF-β-induced apoptosis. These observations offer a harmonious explanation for how a single TAK1 kinase can mediate the opposing responses of cell survival and apoptosis in response to TGF-β. They also reveal a propensity of the alternatively spliced TAK1 isoform TAK1∆E12 to cause drug resistance due to its activity in supporting EMT and NF-κB survival signaling.

中文翻译：

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TGF-β诱导的TAK1选择性剪接促进EMT和耐药性。

转化生长因子-β（TGF-β）是上皮-间质转化（EMT）的主要诱导剂，其通过转录和非转录机制与癌细胞转移以及对化疗药物和靶向药物的耐药性相关。我们先前曾报道过，在癌细胞中，促有丝分裂信号的增强使TGF-β激活的Smad3与poly（RC）结合蛋白1（PCBP1）相互作用，并且它们共同调节了许多选择性的剪接事件，这些事件促进了EMT必需的蛋白亚型的表达，细胞骨架重排，并粘附连接信号。在这里，我们显示排除TGF-β激活激酶1（TAK1）可变外显子12需要另一个RNA结合蛋白Fox-1同系物2（Rbfox2），它独立于Smad3-结合外显子12前面的内含子序列。 PCBP1复合体。在功能上 外显子12排除的TAK1∆E12和全长TAK1FL是不同的。短同工型TAK1∆E12具有组成性活性，支持TGF-β诱导的EMT和核因子κB（NF-κB）信号传导，而全长同工型TAK1FL促进TGF-β诱导的细胞凋亡。这些观察结果为单个TAK1激酶如何介导针对TGF-β的细胞存活和凋亡的相反反应提供了和谐的解释。他们还揭示了由于其支持EMT和NF-κB存活信号的活性，TAS1异构体TAK1E12可能会引起耐药性。而全长同工型TAK1FL则促进TGF-β诱导的细胞凋亡。这些观察结果为单个TAK1激酶如何介导针对TGF-β的细胞存活和凋亡的相反反应提供了和谐的解释。他们还揭示了由于其支持EMT和NF-κB存活信号的活性，TAS1异构体TAK1E12可能会引起耐药性。而全长同工型TAK1FL则促进TGF-β诱导的细胞凋亡。这些观察结果为单个TAK1激酶如何介导针对TGF-β的细胞存活和凋亡的相反反应提供了和谐的解释。他们还揭示了由于其支持EMT和NF-κB存活信号的活性，TAS1异构体TAK1E12可能会引起耐药性。