title: Ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4) by Smad ubiquitination regulatory factor 1 (Smurf1) regulates motility of breast epithelial and cancer cells.
abstract: Smad ubiquitin regulatory factors (Smurfs) are HECT-domain ubiquitin E3 ligases that regulate diverse cellular processes, including normal and tumor cell migration. However, the underlying mechanism of the Smurfs' role in cell migration is not fully understood. Here we show that Smurf1 induces ubiquitination of tumor necrosis factor receptor-associated factor 4 (TRAF4) at K190. Using the K190R mutant of TRAF4, we demonstrate that Smurf1-induced ubiquitination is required for proper localization of TRAF4 to tight junctions in confluent epithelial cells. We further show that TRAF4 is essential for the migration of both normal mammary epithelial and breast cancer cells. The ability of TRAF4 to promote cell migration is also dependent on Smurf1-mediated ubiquitination, which is associated with Rac1 activation by TRAF4. These results reveal a new regulatory circuit for cell migration, consisting of Smurf1-mediated ubiquitination of TRAF4 and Rac1 activation.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Xiangchun
authors.initials: X
authors.lastname: Wang
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Jin
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.forename: Liu-Ya
authors.initials: LY
authors.lastname: Tang
authors.forename: Ying E
authors.initials: YE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D034622:RNA Interference; D053449:TNF Receptor-Associated Factor 4 / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D053449:TNF Receptor-Associated Factor 4; D049452:Green Fluorescent Proteins; C498342:SMURF1 protein, human; D044767:Ubiquitin-Protein Ligases; D020830:rac1 GTP-Binding Protein; D008239:Lysine
keywords: Breast Cancer; Cell Migration; E3 Ubiquitin Ligase; Monoubiquitination; Rac1; Smurf1; TRAF; TRAF4; Tight Junctions; Ubiquitination