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TGF-β-induced alternative splicing of TAK1 promotes EMT and drug resistance

Veenu Tripathi1, Jee-Hye Shin1, Christina H Stuelten1

  • 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Oncogene
|January 11, 2019
PubMed

Insights

Transforming growth factor-β (TGF-β) induces epithelial-to-mesenchymal transition (EMT) and drug resistance. We found a novel mechanism involving RNA-binding proteins that controls TGF-β-activated kinase 1 (TAK1) splicing, impacting cancer cell survival and apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Transforming growth factor-β (TGF-β) is a key regulator of epithelial-to-mesenchymal transition (EMT), a process linked to cancer metastasis and therapeutic resistance.
  • Previous work identified Smad3 and PCBP1 complex regulating alternative splicing in response to TGF-β, favoring EMT-associated isoforms.
  • The distinct roles of TGF-β-activated kinase 1 (TAK1) isoforms in cellular responses remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanism controlling the alternative splicing of TAK1 in response to TGF-β.
  • To characterize the distinct functions of TAK1 isoforms generated by alternative splicing.
  • To understand the contribution of TAK1 splicing to TGF-β-mediated cellular outcomes, including EMT and drug resistance.

Main Methods:

  • RNA-binding protein immunoprecipitation (RIP).
  • Analysis of alternative splicing events using molecular biology techniques.
  • Functional assays assessing cell signaling pathways (EMT, NF-κB) and apoptosis.
  • Western blotting to detect protein isoforms.

Main Results:

  • The RNA-binding protein Rbfox2 mediates the exclusion of TGF-β-activated kinase 1 (TAK1) exon 12, independent of the Smad3-PCBP1 complex.
  • The alternatively spliced TAK1 isoform lacking exon 12 (TAK1∆E12) is constitutively active and promotes TGF-β-induced EMT and nuclear factor kappa B (NF-κB) signaling.
  • The full-length TAK1 isoform (TAK1FL) promotes TGF-β-induced apoptosis, while TAK1∆E12 confers resistance to chemotherapy and targeted drugs by supporting EMT and NF-κB survival signaling.

Conclusions:

  • A novel splicing mechanism involving Rbfox2 controls TAK1 isoform expression in response to TGF-β.
  • Distinct TAK1 isoforms mediate opposing cellular responses: TAK1∆E12 promotes survival and EMT, while TAK1FL promotes apoptosis.
  • The alternatively spliced TAK1∆E12 isoform is a potential driver of drug resistance in cancer through its pro-EMT and pro-survival signaling activities.

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