title: Reversible SUMOylation of TBL1-TBLR1 regulates β-catenin-mediated Wnt signaling.
abstract: Dysregulation of Wnt signaling has been implicated in tumorigenesis. The role of Transducin β-like proteins TBL1-TBLR1 in the promotion of Wnt/β-catenin-mediated oncogenesis has recently been emphasized; however, the molecular basis of activation of Wnt signaling by the corepressor TBL1-TBLR1 is incompletely understood. Here, we show that both TBL1 and TBLR1 are SUMOylated in a Wnt signaling-dependent manner, and that this modification is selectively reversed by SUMO-specific protease I (SENP1). SUMOylation dismissed TBL1-TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex, increased recruitment of the TBL1-TBLR1-β-catenin complex to the promoter of Wnt target genes, and consequently led to activation of Wnt signaling. Conversely, SENP1 decreased formation of the TBL1-TBLR1-β-catenin complex, leading to inhibition of β-catenin-mediated transcription. Importantly, inhibition of SUMOylation significantly decreased the tumorigenicity of SW480 colon cancer cells. Thus, our data reveal a mechanism for activation of Wnt signaling via the SUMOylation-dependent disassembly of the corepressor complex.
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Chronic Metabolic Disease Research, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hyo-Kyoung
authors.initials: HK
authors.lastname: Choi
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Yoo
authors.forename: Meiying
authors.initials: M
authors.lastname: Song
authors.forename: Suk Jin
authors.initials: SJ
authors.lastname: Ko
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.forename: Jin-Hyun
authors.initials: JH
authors.lastname: Ahn
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
authors.forename: Jong In
authors.initials: JI
authors.lastname: Yook
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D016475:3T3 Cells; D000818:Animals; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D015293:Transducin / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C473691:TBL1XR1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D015293:Transducin