title: Reciprocal regulation between βTrCP and Smurf1 suppresses proliferative capacity of liver cancer cells.
abstract: We previously reported that both the ubiquitin E3 ligases βTrCP (beta-transducin repeat-containing E3 ubiquitin protein ligase) and Smurf1 (SMAD-specific E3 ubiquitin protein ligase 1) play similar antitumorigenic roles in liver cancer cells. However, whether and how they are reciprocally regulated remains elusive. Here, we show that βTrCP interacts with Smurf1 through the 7 × tryptophan (W) aspartic acid (D)(WD) 40 and the region homologous to the E6-AP carboxyl terminus (HECT) domains, which are the E3 ligase domains of βTrCP and Smurf1, respectively. The E3 ligase domains of βTrCP and Smurf1 are also critical for maintaining the protein expressions of Smurf1 and βTrCP. Moreover, a positive correlation between βTrCP and Smurf1 was also revealed by tissue microarray analysis, indicating that this relationship might be important in liver cancer. Further, we found that Smurf1 increases the protein stability of βTrCP, possibly by reducing autoubiquitination of βTrCP, and vice versa. Interestingly, such effects depended on the presence of E3 ligase domains. Importantly, depletion of Smurf1- or βTrCP-enhanced proliferative capacity of liver cancer cells could be partially reversed by overexpression of wild-type βTrCP or Smurf1 but not their E3 ligase-dead mutants. Collectively, a reciprocal post-translational regulation between βTrCP and Smurf1 has been uncovered in this study. Simultaneous enhancement of βTrCP and Smurf1 functions might be helpful in the treatment of liver cancer.
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Si
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Qinwan
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Qiuhui
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.
authors.forename: Fenyong
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China.|Advanced Institute of Translational Medicine, Tongji University, Shanghai, China.
authors.forename: Jiayi
authors.identifier: http://orcid.org/0000-0002-8500-5518
authors.initials: J
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D044844:beta-Transducin Repeat-Containing Proteins; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: E3 ubiquitin ligase; post-translational modification; protein stability; tumor suppressor gene; ubiquitination