TRB3 interacts with SMAD3 promoting tumor cell migration and invasion
| Autor: | Zhuowei Hu, Jianfei Xue, Jinwen Liu, Heng Lin, Ziyan Wang, Hong-Zhen Yang, Xiaoguang Chen, Fang Hua, Rong Mu |
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| Rok vydání: | 2011 |
| Předmět: |
Transcriptional Activation
Cell signaling Epithelial-Mesenchymal Transition Ubiquitin-Protein Ligases Cell Cycle Proteins SMAD Protein Serine-Threonine Kinases Ubiquitin Cell Movement Genes Reporter RNA interference Humans Neoplasm Invasiveness Smad3 Protein Promoter Regions Genetic Luciferases Renilla Cell Nucleus Gene knockdown integumentary system biology Hep G2 Cells Cell Biology Cadherins Actins Transport protein Cell biology Repressor Proteins Protein Transport TRIB3 Gene Knockdown Techniques Proteolysis biology.protein Phosphorylation RNA Interference biological phenomena cell phenomena and immunity |
| Zdroj: | Journal of Cell Science. 124:3235-3246 |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.082875 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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