Journal ArticleDOI
RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling.
Yue Zhang,Shanming Liu,Craig Mickanin,Yan Feng,Olga Charlat,Gregory A. Michaud,Markus Schirle,Xiaoying Shi,Marc Hild,Andreas Bauer,Vic E. Myer,Peter Finan,Jeffery A. Porter,Shih-Min A. Huang,Feng Cong +14 more
TLDR
Identification of RNF146, a RING-domain E3 ubiquitin ligase, as a PARsylation-directed E3 ligase establishes a molecular paradigm that links tankyrase-dependent poly(ADP-ribosyl)ation to ubiquitylation and degradation of axin.Abstract:
The Wnt/β-catenin signalling pathway plays essential roles in embryonic development and adult tissue homeostasis, and deregulation of this pathway has been linked to cancer. Axin is a concentration-limiting component of the β-catenin destruction complex, and its stability is regulated by tankyrase. However, the molecular mechanism by which tankyrase-dependent poly(ADP-ribosyl)ation (PARsylation) is coupled to ubiquitylation and degradation of axin remains undefined. Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. Thus, identification of RNF146 as a PARsylation-directed E3 ligase establishes a molecular paradigm that links tankyrase-dependent PARsylation to ubiquitylation. RNF146-dependent protein degradation may emerge as a major mechanism by which tankyrase exerts its function.read more
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Journal ArticleDOI
New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs.
Bryan A. Gibson,W. Lee Kraus +1 more
TL;DR: This work has shown that the activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and through poly(ADP-ribosyl)ation (PARylation) they ultimately promote changes in gene expression, RNA and protein abundance, and the location and activity of proteins that mediate signalling responses.
Journal ArticleDOI
Ubiquitin Ligases: Structure, Function, and Regulation
Ning Zheng,Nitzan Shabek +1 more
TL;DR: Current progress in structure-function studies of ubiquitin ligases as well as exciting new discoveries of novel classes of E3s and diverse substrate recognition mechanisms are summarized.
Journal ArticleDOI
ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
Huaixiang Hao,Yang Xie,Yue Zhang,Yue Zhang,Olga Charlat,Emma Oster,Monika Avello,Hong Lei,Craig Mickanin,Dong Liu,Heinz Ruffner,Xiaohong Mao,Qicheng Ma,Raffaella Zamponi,Tewis Bouwmeester,Peter Finan,Marc W. Kirschner,Jeffery A. Porter,Fabrizio C. Serluca,Feng Cong +19 more
TL;DR: It is shown that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling, and R-spondin mimics ZNRF3 inhibition by increasing the membrane level of WNT receptors.
Journal ArticleDOI
On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1
Xin Luo,W. Lee Kraus +1 more
TL;DR: This review of recent studies in cell and animal models highlights the newest findings about PARP-1's role in stress responses in the context of the historical data.
Journal ArticleDOI
Wnt signaling in stem and cancer stem cells.
TL;DR: Intensive work is currently being performed to resolve how intrinsic and extrinsic factors that regulate Wnt/β-catenin signaling coordinate the stem and cancer stem cell states.
References
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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
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