title: The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial-mesenchymal transition in a sumoylation-regulated manner.
abstract: Epithelial-mesenchymal transition (EMT) is a fundamental cellular process in epithelial tissue development, and can be reactivated in cancer contributing to tumor invasiveness and metastasis. The cytokine transforming growth factor-β (TGFβ) is a key inducer of EMT, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Here, we report that knockdown of the ubiquitin ligase Smurf2 promotes the ability of TGFβ to induce EMT in a three-dimensional cell culture model of NMuMG mammary epithelial cells. In other studies, we identify Smurf2 as a target of the small ubiquitin like modifier (SUMO) pathway. We find that the SUMO-E2 conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS3 associate with Smurf2 and promote its sumoylation at the distinct sites of Lysines 26 and 369. The sumoylation of Smurf2 enhances its ability to induce the degradation of the TGFβ receptor and thereby suppresses EMT in NMuMG cells. Collectively, our data reveal that Smurf2 acts in a sumoylation-regulated manner to suppress TGFβ-induced EMT. These findings have significant implications for our understanding of epithelial tissue development and cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors.forename: A S
authors.initials: AS
authors.lastname: Chandhoke
authors.affiliation: Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Karve
authors.affiliation: Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Dadakhujaev
authors.affiliation: Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Netherton
authors.affiliation: Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Molecular Biology, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Bonni
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D058207:Sumoylation; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D016212:Transforming Growth Factor beta; D044763:Ubiquitin-Conjugating Enzymes; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D000098843:Ubiquitin-Conjugating Enzyme UBC9