title: Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling.
abstract: The Tcf/Lef family of transcription factors mediates the Wnt/β-catenin pathway that is involved in a wide range of biological processes, including vertebrate embryogenesis and diverse pathogenesis. Post-translational modifications, including phosphorylation, sumoylation and acetylation, are known to be important for the regulation of Tcf/Lef proteins. However, the importance of ubiquitination and ubiquitin-mediated regulatory mechanisms for Tcf/Lef activity are still unclear. Here, we newly show that ubiquitin C-terminal hydrolase 37 (Uch37), a deubiquitinase, interacts with Tcf7 (formerly named Tcf1) to activate Wnt signalling. Biochemical analyses demonstrated that deubiquitinating activity of Uch37 is not involved in Tcf7 protein stability but is required for the association of Tcf7 to target gene promoter in both Xenopus embryo and human liver cancer cells. In vivo analyses further revealed that Uch37 functions as a positive regulator of the Wnt/β-catenin pathway downstream of β-catenin stabilization that is required for the expression of ventrolateral mesoderm genes during Xenopus gastrulation. Our study provides a new mechanism for chromatin occupancy of Tcf7 and uncovers the physiological significance of Uch37 during early vertebrate development by regulating the Wnt/β-catenin pathway.
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Korea.
authors.forename: Hyeyoon
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Life Sciences, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk, 37673, Korea.
authors.forename: Jin-Kwan
authors.initials: JK
authors.lastname: Han
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability; D051822:T Cell Transcription Factor 1 / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D060449:Wnt Signaling Pathway; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D029867:Xenopus Proteins; D051176:beta Catenin; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase