Loss of Tankyrase-Mediated Destruction of 3BP2 Is the Underlying Pathogenic Mechanism of Cherubism
| Autor: | Jose La Rose, Andrew Scotter, Marcel Deckert, Fabrice Sircoulomb, Yasuyoshi Ueki, Paul D. Simoncic, Feng Cong, Noam Levaot, Ioannis D. Dimitriou, Robert Rottapel, Shengqing Gu, Oleksandr Voytyuk, Arun A. Chandrakumar, Paul M. Krzyzanowski, Salima Janmohamed |
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| Rok vydání: | 2011 |
| Předmět: |
Lineage (genetic)
Syk Osteoclasts Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Ubiquitin SH3BP2 medicine Animals Humans Syk Kinase Proto-Oncogene Proteins c-vav 030304 developmental biology Adaptor Proteins Signal Transducing Sequence Deletion 0303 health sciences Tankyrases Protein Stability Tumor Necrosis Factor-alpha Biochemistry Genetics and Molecular Biology(all) Macrophages Intracellular Signaling Peptides and Proteins Ubiquitination Signal transducing adaptor protein Cherubism Protein-Tyrosine Kinases medicine.disease Disease Models Animal 030220 oncology & carcinogenesis Cancer research biology.protein Signal transduction Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Zdroj: | Cell. 147(6):1324-1339 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2011.10.045 |
| Popis: | SUMMARY 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. |
| Databáze: | OpenAIRE |
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