@article{bab4f54428874f77ae5fbf00a7689516,
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.",
author = "Noam Levaot and Oleksandr Voytyuk and Ioannis Dimitriou and Fabrice Sircoulomb and Arun Chandrakumar and Marcel Deckert and Krzyzanowski, {Paul M.} and Andrew Scotter and Shengqing Gu and Salima Janmohamed and Feng Cong and Simoncic, {Paul D.} and Yasuyoshi Ueki and {La Rose}, Jose and Robert Rottapel",
note = "Funding Information: This work was supported by a grant from the Terry Fox Research Institute (TFPP Grant #20003), by the Canadian Cancer Society Research Institute, and by the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the OMOHLTC. R.R. is supported by the Amgen Chair for Cancer Research from the PMHF at the Ontario Cancer Institute, Princess Margaret Hospital. N.L. was supported by the Arthritis Centre for Excellence Fellowship, University of Toronto. Y.U. was supported by the Charles H. Hood Foundation, Inc., Boston, MA and research grant R01DE020835 from the National Institutes of Health. We thank Gerald Gish for providing the peptides and Sebastian Geuttler for assistance with the fluorescence polarization experiments. We thank Ben Neel and Norman Iscove for discussion regarding the chimera experiments. We thank Mauricio Medrano for graphic design. We thank Frank Sicheri, Sebastian Geuttler, Ernst Reichenberger, Gregg Morin, Vuk Stambolic, and Ben Neel for critical reading of the manuscript. ",
year = "2011",
month = dec,
day = "9",
doi = "10.1016/j.cell.2011.10.045",
language = "English",
volume = "147",
pages = "1324--1339",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}