Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism

Noam Levaot, Oleksandr Voytyuk, Ioannis Dimitriou, Fabrice Sircoulomb, Arun Chandrakumar, Marcel Deckert, Paul M. Krzyzanowski, Andrew Scotter, Shengqing Gu, Salima Janmohamed, Feng Cong, Paul D. Simoncic, Yasuyoshi Ueki, Jose La Rose, Robert Rottapel

Research output: Contribution to journalArticle

103 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1324-1339
Number of pages16
JournalCell
Volume147
Issue number6
DOIs
StatePublished - Dec 9 2011
Externally publishedYes

Fingerprint

Tankyrases
Cherubism
Bone
Ubiquitin-Protein Ligases
Poly(ADP-ribose) Polymerases
Mutation
Adenosine Diphosphate
Osteoclasts
Proteins
Stabilization
Genes
Peptides
Facial Bones
Bone Remodeling
Ubiquitination
Inflammation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Levaot, N., Voytyuk, O., Dimitriou, I., Sircoulomb, F., Chandrakumar, A., Deckert, M., ... Rottapel, R. (2011). Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell, 147(6), 1324-1339. https://doi.org/10.1016/j.cell.2011.10.045

Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. / Levaot, Noam; Voytyuk, Oleksandr; Dimitriou, Ioannis; Sircoulomb, Fabrice; Chandrakumar, Arun; Deckert, Marcel; Krzyzanowski, Paul M.; Scotter, Andrew; Gu, Shengqing; Janmohamed, Salima; Cong, Feng; Simoncic, Paul D.; Ueki, Yasuyoshi; La Rose, Jose; Rottapel, Robert.

In: Cell, Vol. 147, No. 6, 09.12.2011, p. 1324-1339.

Research output: Contribution to journalArticle

Levaot, N, Voytyuk, O, Dimitriou, I, Sircoulomb, F, Chandrakumar, A, Deckert, M, Krzyzanowski, PM, Scotter, A, Gu, S, Janmohamed, S, Cong, F, Simoncic, PD, Ueki, Y, La Rose, J & Rottapel, R 2011, 'Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism', Cell, vol. 147, no. 6, pp. 1324-1339. https://doi.org/10.1016/j.cell.2011.10.045
Levaot N, Voytyuk O, Dimitriou I, Sircoulomb F, Chandrakumar A, Deckert M et al. Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. Cell. 2011 Dec 9;147(6):1324-1339. https://doi.org/10.1016/j.cell.2011.10.045
Levaot, Noam ; Voytyuk, Oleksandr ; Dimitriou, Ioannis ; Sircoulomb, Fabrice ; Chandrakumar, Arun ; Deckert, Marcel ; Krzyzanowski, Paul M. ; Scotter, Andrew ; Gu, Shengqing ; Janmohamed, Salima ; Cong, Feng ; Simoncic, Paul D. ; Ueki, Yasuyoshi ; La Rose, Jose ; Rottapel, Robert. / Loss of Tankyrase-mediated destruction of 3BP2 is the underlying pathogenic mechanism of cherubism. In: Cell. 2011 ; Vol. 147, No. 6. pp. 1324-1339.
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