Trkb-induced inhibition of R-SMAD/SMAD4 activation is essential for TGF-β-mediated tumor suppressor activity
- Authors
- Kim M.S.; Jin W.
- Issue Date
- Apr-2020
- Publisher
- MDPI AG
- Keywords
- Transforming growth factor-β (TGF-β); TrkB; Tumor progression; Tumor suppressor activity
- Citation
- Cancers, v.12, no.4
- Journal Title
- Cancers
- Volume
- 12
- Number
- 4
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/51604
- DOI
- 10.3390/cancers12041048
- ISSN
- 2072-6694
- Abstract
- TrkB-mediated activation of the IL6/JAK2/STAT3 signaling pathway is associated with the induction of the epithelial–mesenchymal transition (EMT) program and the acquisition of metastatic potential by tumors. Conversely, the transforming of growth factor-β (TGF-β) is implicated in tumor suppression through the canonical SMAD-dependent signaling pathway. Hence, TrkB could play a role in disrupting the potent TGF-β-mediated growth inhibition, a concept that has not been fully explored. Here, we identified TrkB to be a crucial regulator of the TGF-β signaling pathway as it inhibits the TGF-β-mediated tumor suppression and the activation of TrkB kinase. We further show that the interactions between TrkB and SMADs inhibit TGF-β-mediated R-SMAD/SMAD4 complex formation and suppress TGF-β-induced nuclear translocation and target gene expression. Additionally, the knockdown of TrkB restored the tumor inhibitory activity of TGF-β signaling. These observations suggest that interactions between TrkB and SMADs are critical for the inhibition of TGF-β tumor suppressor activity in cancer cells. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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