Reversible SUMOylation of TBL1-TBLR1 Regulates β-Catenin-Mediated Wnt Signaling

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 inc...

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Published in:Molecular cell 2011-07, Vol.43 (2), p.203-216
Main Authors: Choi, Hyo-Kyoung, Choi, Kyung-Chul, Yoo, Jung-Yoon, Song, Meiying, Ko, Suk Jin, Kim, Chul Hoon, Ahn, Jin-Hyun, Chun, Kyung-Hee, Yook, Jong In, Yoon, Ho-Geun
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
beta Catenin - genetics
beta Catenin - metabolism
carcinogenesis
colorectal neoplasms
genes
hormone receptors
Humans
inhibition
Mice
neoplasm cells
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
proteinases
Receptors, Cytoplasmic and Nuclear - metabolism
Repressor Proteins - metabolism
Signal Transduction
Sumoylation
Transducin - genetics
Transducin - metabolism
Transfection
Tumor Cells, Cultured
Wnt Proteins - genetics
Wnt Proteins - metabolism
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Summary: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. ► Both TBL1 and TBLR1 are SUMOylated in a Wnt signaling-dependent manner ► SUMOylation dismissed TBL1-TBLR1 from the NCoR/SMRT corepressor complexes ► SENP1-mediated deSUMOylation decreased formation of the TBL1-TBLR1-β-catenin complex ► DeSUMOylation of TBL1-TBLR1 suppressed the tumorigenicity of SW480 colon cancer cells
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2011.05.027