title: RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling.
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.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shanming
authors.initials: S
authors.lastname: Liu
authors.forename: Craig
authors.initials: C
authors.lastname: Mickanin
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Olga
authors.initials: O
authors.lastname: Charlat
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michaud
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shi
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.forename: Vic E
authors.initials: VE
authors.lastname: Myer
authors.forename: Peter M
authors.initials: PM
authors.lastname: Finan
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Porter
authors.forename: Shih-Min A
authors.initials: SM
authors.lastname: Huang
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060466:Axin Protein; D012097:Repressor Proteins; D051153:Wnt Proteins; D011064:Poly Adenosine Diphosphate Ribose; D044767:Ubiquitin-Protein Ligases