TRB3 interacts with SMAD3 promoting tumor cell migration and invasion.

Fang Hua, Rong Mu, Jinwen Liu, Jianfei Xue, Ziyan Wang, Heng Lin, Hongzhen Yang, Xiaoguang Chen, Zhuowei Hu

Molecular Immunology and Pharmacology Laboratory, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing, 100050, P R China.

Journal of cell science 2011 Oct 1

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Tribbles homolog 3 (TRB3, also known as TRIB3, NIPK and SKIP3), a human homolog of Drosophila Tribbles, has been found to interact with a variety of signaling molecules to regulate diverse cellular functions. Here, we report that TRB3 is a novel SMAD3-interacting protein. Expression of exogenous TRB3 enhanced the transcriptional activity of SMAD3, whereas knocking down endogenous TRB3 reduced the transcriptional activity of SMAD3. The kinase-like domain (KD) of TRB3 was responsible for the interaction with SMAD3 and the regulation of SMAD3-mediated transcriptional activity. In addition, TGF-β1 stimulation or overexpression of SMAD3 enhanced the TRB3 promoter activity and expression, suggesting that there is a positive feedback loop between TRB3 and TGF-β-SMAD3 signaling. Mechanistically, TRB3 was found to trigger the degradation of SMAD ubiquitin regulatory factor 2 (Smurf2), which resulted in a decrease in the degradation of SMAD2 and phosphorylated SMAD3. Moreover, TRB3-SMAD3 interaction promoted the nuclear localization of SMAD3 because of the interaction of TRB3 with the MH2 domain of SMAD3. These effects of TRB3 were responsible for potentiating the SMAD3-mediated activity. Furthermore, knockdown of endogenous TRB3 expression inhibited the migration and invasion of tumor cells in vitro, which were associated with an increase in the expression of E-cadherin and a decrease in the expression of Twist-1 and Snail, two master regulators of epithelial-to-mesenchymal transition, suggesting a crucial role for TRB3 in maintaining the mesenchymal status of tumor cells. These results demonstrate that TRB3 acts as a novel SMAD3-interacting protein to participate in the positive regulation of TGF-β-SMAD-mediated cellular biological functions. @ 2011. Published by The Company of Biologists Ltd

Citation

Fang Hua, Rong Mu, Jinwen Liu, Jianfei Xue, Ziyan Wang, Heng Lin, Hongzhen Yang, Xiaoguang Chen, Zhuowei Hu. TRB3 interacts with SMAD3 promoting tumor cell migration and invasion. Journal of cell science. 2011 Oct 1;124(Pt 19):3235-46