HAT cofactor TRRAP mediates beta-catenin ubiquitination on the chromatin and the regulation of the canonical Wnt pathway.
The Wnt pathway is a key regulator of embryonic development and stem cell self-renewal, and hyperactivation of the Wnt signalling is associated with many human cancers. The central player in the Wnt pathway is beta-catenin, a cytoplasmic protein whose function is tightly controlled by ubiquitination and degradation, however the precise regulation of beta-catenin stability/degradation remains elusive. Here, we report a new mechanism of beta-catenin ubiquitination acting in the context of chromatin. This mechanism is mediated by the histone acetyltransferase (HAT) complex component TRRAP and Skp1, an invariable component of the Skp-Cullin-F-box (SCF) ubiquitin ligase complex. TRRAP interacts with Skp1/SCF and mediates its recruitment to beta-catenin target promoter in chromatin. TRRAP deletion leads to a reduced level of beta-catenin ubiquitination, lower degradation rate and accumulation of beta-catenin protein. Furthermore, recruitment of Skp1 to chromatin and ubiquitination of chromatin-bound beta-catenin are abolished upon TRRAP knock-down, leading to an abnormal retention of beta-catenin at the chromatin and concomitant hyperactivation of the canonical Wnt pathway. These results demonstrate that there is a distinct regulatory mechanism for beta-catenin ubiquitination/ destruction acting in the nucleus which functionally complements cytoplasmic destruction of beta-catenin and prevents its oncogenic stabilization and chronic activation of the canonical Wnt pathway.
Finkbeiner
Martin G
MG
International Agency for Research on Cancer (IARC), Lyon, France.
Sawan
Carla
C
Ouzounova
Maria
M
Murr
Rabih
R
Herceg
Zdenko
Z
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C113829:transformation-transcription domain-associated protein; D051548:Histone Acetyltransferases