Abstract
Smad and STAT proteins are critical signal transducers and transcription factors in controlling cell growth and tumorigenesis. Here we report that the STAT3 signaling pathway attenuates transforming growth factor-β (TGF-β)-induced responses through a direct Smad3–STAT3 interplay. Activated STAT3 blunts TGF-β-mediated signaling. Depletion of STAT3 promotes TGF-β-mediated transcriptional and physiological responses, including cell cycle arrest, apoptosis and epithelial-to-mesenchymal transition. STAT3 directly interacts with Smad3 in vivo and in vitro, resulting in attenuation of the Smad3–Smad4 complex formation and suppression of DNA-binding ability of Smad3. The N-terminal region of DNA-binding domain of STAT3 is responsible for the STAT3–Smad3 interaction and also indispensable for STAT3-mediated inhibition of TGF-β signaling. Thus, our finding illustrates a direct crosstalk between the STAT3 and Smad3 signaling pathways that may contribute to tumor development and inflammation.
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Acknowledgements
We thank David Luskutoff for p800 (PAI-1)-luc, Peter ten Dijke for CAGA-luc, Bert Vogelstein for WWP1 (p21)-luc and SBE-luc and Xiao-Fan Wang for p15-luc. We are grateful to colleagues in our laboratories for helpful discussion and technical assistance. This research was partly supported by grants from MOST (2012CB966600) and NSFC (31571447; 31090360), NIH (R01GM63773, R01 AR053591, R01CA108454 and R01DK073932), Project 111, Project 985 and the Fundamental Research Funds for the Central Universities.
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Wang, G., Yu, Y., Sun, C. et al. STAT3 selectively interacts with Smad3 to antagonize TGF-β. Oncogene 35, 4388–4398 (2016). https://doi.org/10.1038/onc.2015.446
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DOI: https://doi.org/10.1038/onc.2015.446
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