title: Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism.
abstract: Cherubism is an autosomal-dominant syndrome characterized by inflammatory destructive bony lesions resulting in symmetrical deformities of the facial bones. Cherubism is caused by mutations in Sh3bp2, the gene that encodes the adaptor protein 3BP2. Most identified mutations in 3BP2 lie within the peptide sequence RSPPDG. A mouse model of cherubism develops hyperactive bone-remodeling osteoclasts and systemic inflammation characterized by expansion of the myelomonocytic lineage. The mechanism by which cherubism mutations alter 3BP2 function has remained obscure. Here we show that Tankyrase, a member of the poly(ADP-ribose)polymerase (PARP) family, regulates 3BP2 stability through ADP-ribosylation and subsequent ubiquitylation by the E3-ubiquitin ligase RNF146 in osteoclasts. Cherubism mutations uncouple 3BP2 from Tankyrase-mediated protein destruction, which results in its stabilization and subsequent hyperactivation of the SRC, SYK, and VAV signaling pathways.
authors.affiliation: Ontario Cancer Institute and the Campbell Family Cancer Research Institute, 101 College Street, Rm 8-703, Toronto Medical Discovery Tower, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Noam
authors.initials: N
authors.lastname: Levaot
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Voytyuk
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dimitriou
authors.forename: Fabrice
authors.initials: F
authors.lastname: Sircoulomb
authors.forename: Arun
authors.initials: A
authors.lastname: Chandrakumar
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
authors.forename: Paul M
authors.initials: PM
authors.lastname: Krzyzanowski
authors.forename: Andrew
authors.initials: A
authors.lastname: Scotter
authors.forename: Shengqing
authors.initials: S
authors.lastname: Gu
authors.forename: Salima
authors.initials: S
authors.lastname: Janmohamed
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
authors.forename: Paul D
authors.initials: PD
authors.lastname: Simoncic
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Ueki
authors.forename: Jose
authors.initials: J
authors.lastname: La Rose
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002636:Cherubism / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D000072377:Syk Kinase; D038501:Tankyrases / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D051567:Proto-Oncogene Proteins c-vav; C484644:Sh3bp2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D038501:Tankyrases; C511054:tankyrase-2, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse