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PAK5-mediated E47 phosphorylation promotes epithelial–mesenchymal transition and metastasis of colon cancer

Oncogene volume 35, pages 1943–1954 (2016)Cite this article

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Abstract

The p21-activated kinase 5 (PAK5) is overexpressed in advanced cancer and the transcription factor E47 is a direct repressor of E-cadherin and inducer of epithelial–mesenchymal transition (EMT). However, the relationship between PAK5 and E47 has not been explored. In this study, we found that PAK5-mediated E47 phosphorylation promoted EMT in advanced colon cancer. PAK5 interacted with E47 and phosphorylated E47 on Ser39 under hepatocyte growth factor (HGF) stimulation, which decreased cell–cell cohesion, increased cell migration and invasion in vitro and promoted metastasis in a xenograft model. Furthermore, phosphorylation of E47 facilitated its accumulating in nucleus in an importin α-dependent manner, and enhanced E47 binding to E-cadherin promoter directly, leading to inhibition of E-cadherin transcription. In contrast, PAK5-knockdown resulted in blockage of HGF-induced E47 phosphorylation, attenuated association of E47 with importin α and decreased E47 binding to E-cadherin promoter. In addition, we demonstrated a close correlation between PAK5 and phospho-Ser39 E47 expression in colon cancer specimens. More importantly, high expression of phospho-E47 was associated with an aggressive phenotype of colon cancer and nuclear phospho-E47 staining was found in certain cases of colon cancer with metastasis. Collectively, E47 is a novel substrate of PAK5, and PAK5-mediated phosphorylation of E47 promotes EMT and metastasis of colon cancer, suggesting that phosphorylated E47 on Ser39 may be a potential therapeutic target in progressive colon cancer.

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Acknowledgements

We are grateful to Drs Stephen J Brandt and Akira Kato for providing essential expression vectors. We also thank Dr Funan Liu for technical assistance. This work was supported by grants from the National Natural Science Foundation of China (Nos 90813038, 31371424, 31171360, 31000627, 81201659 and 81230077), Doctoral fund of Ministry of Education of China (No. 20102104110016) and Ministry of Education of China (IRT 13101).

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Authors and Affiliations

  1. Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China

    G Zhu, X Li, B Guo & F Li

  2. Department of Diagnostics, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China

    Q Ke

  3. Department of General Surgery, Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, China

    M Dong

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Correspondence to F Li.

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Zhu, G., Li, X., Guo, B. et al. PAK5-mediated E47 phosphorylation promotes epithelial–mesenchymal transition and metastasis of colon cancer. Oncogene 35, 1943–1954 (2016). https://doi.org/10.1038/onc.2015.259

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