title: PAK5-mediated E47 phosphorylation promotes epithelial-mesenchymal transition and metastasis of colon cancer.
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.
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: B
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Diagnostics, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of General Surgery, Gastrointestinal Surgery, The First Hospital, China Medical University, Shenyang, China.
authors.forename: M
authors.initials: M
authors.lastname: Dong
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Li
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D058127:Transcription Factor 3 / Q000378:metabolism*; D014158:Transcription, Genetic; D028901:alpha Karyopherins / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D015820:Cadherins; D002867:Chromones; C423142:KPNA1 protein, human; D009025:Morpholines; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D058127:Transcription Factor 3; D028901:alpha Karyopherins; D010768:Phosphoserine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017228:Hepatocyte Growth Factor; C443802:PAK5 protein, human; D054462:p21-Activated Kinases