title: Phosphorylation of ETV4 at Ser73 by ERK kinase could block ETV4 ubiquitination degradation in colorectal cancer.
abstract: It was reported that Src-mediated and RTK-dependent accumulation of key transcription factor, ETV4, which played an important role in the migration of embryonic cells and tumor cells, were regulated by their common downstream MAPK molecules. However, the detailed mechanism was not completely clear. In the present study, we revealed that ETV4 protein was significantly enhanced by ERK kinase activation in the colorectal cancer (CRC) patients and mouse models as well as in the CRC cell lines. It was further confirmed that the activation of ERK kinase led to the phosphorylation of ETV4 at Ser73 and the ETV4 phosphorylation could block its binding to COP1, thereby stabilized ETV4 via avoiding its ubiquitination degradation. In addition, this effect was not due to altering an E3 ubiquitin ligase, COP1 amount or p-COP1/COP1 ratio. Our results will help understand the mechanism of ETV4 overexpression in CRC patients and provide a clue to search new therapeutic target to treat the related tumors in clinical practice.
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Cancer Institute of Capital Medical University, Beijing 100069, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, PR China; Cancer Institute of Capital Medical University, Beijing 100069, PR China.
authors.forename: Shu
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Cancer Institute of Capital Medical University, Beijing 100069, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Shen
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, PR China.
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, PR China; Cancer Institute of Capital Medical University, Beijing 100069, PR China.
authors.forename: Haimei
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, PR China; Cancer Institute of Capital Medical University, Beijing 100069, PR China.
authors.forename: Fengqing
authors.initials: F
authors.lastname: Ji
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, PR China; Cancer Institute of Capital Medical University, Beijing 100069, PR China. Electronic address: zhoudeshan2008@163.com.
authors.forename: Deshan
authors.initials: D
authors.lastname: Zhou
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D017500:Adenovirus E1A Proteins; C079853:ETV4 protein, human; C540571:Etv4 protein, mouse; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D057149:Ubiquitinated Proteins; D014452:Ubiquitins; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: COP1; Colorectal cancer; ETV4; Phosphorylation; Ubiquitination degradation