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Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization

Oncogene volume 35, pages 389–401 (2016)Cite this article

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Abstract

Syntenin, a tandem PDZ domain containing scaffold protein, functions as a positive regulator of cancer cell progression in several human cancers. We report here that syntenin positively regulates transforming growth factor (TGF)-β1-mediated Smad activation and the epithelial-to-mesenchymal transition (EMT) by preventing caveolin-1-mediated internalization of TGF-β type I receptor (TβRI). Knockdown of syntenin suppressed TGF-β1-mediated cell migration, transcriptional responses and Smad2/3 activation in various types of cells; however, overexpression of syntenin facilitated TGF-β1-mediated responses. In particular, syntenin knockdown abolished both the basal and TGF-β1-mediated repression of E-cadherin expression, as well as induction of vimentin expression along with Snail and Slug upregulation; thus, blocking the TGF-β1-induced EMT in A549 cells. In contrast, overexpression of syntenin exhibited the opposite effect. Knockdown of syntenin-induced ubiquitination and degradation of TβRI, but not TGF-β type II receptor, leading to decreased TβRI expression at the plasma membrane. Syntenin associated with TβRI at its C-terminal domain and a syntenin mutant lacking C-terminal domain failed to increase TGF-β1-induced responses. Biochemical analyzes revealed that syntenin inhibited the interaction between caveolin-1 and TβRI and knockdown of syntenin induced a massive internalization of TβRI and caveolin-1 from lipid rafts, indicating that syntenin may increase TGF-β signaling by inhibiting caveolin-1-dependent internalization of TβRI. Moreover, a positive correlation between syntenin expression and phospho-Smad2 levels is observed in human lung tumors. Taken together, these findings demonstrate that syntenin may act as an important positive regulator of TGF-β signaling by regulating caveolin-1-mediated internalization of TβRI; thus, providing a novel function for syntenin that is linked to cancer progression.

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Acknowledgements

This work was supported by grants from the Korean Health Technology R&D Project (A111311), Ministry of Health and Welfare, Republic of Korea and the National Research Foundation of Korea (NRF, 2013R1A1A2009026).

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Authors and Affiliations

  1. Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do, Republic of Korea

    C Hwangbo, N Tae, S Lee, O Kim, J Kim & J-H Lee

  2. Division of Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-Do, Republic of Korea

    O K Park & S-H Kwon

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  1. C Hwangbo
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Hwangbo, C., Tae, N., Lee, S. et al. Syntenin regulates TGF-β1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-β type I receptor internalization. Oncogene 35, 389–401 (2016). https://doi.org/10.1038/onc.2015.100

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