期刊
ONCOTARGET
卷 5, 期 12, 页码 4211-4221出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1971
关键词
beta-TRCP; CYLD; tumor suppressor; degradation; phosphorylation; ubiquitination
资金
- National Institutes of Health (NIH) [GM094777, CA177910]
- Development Program for High-quality professionals and Startup Foundation for Doctors [12-013]
- College of Stomatology, Chongqing Medical University, China
- National Institute on Aging (NIA) [AG041218]
CYLD negatively regulates the NF-kappa B signaling pathway and osteoclast differentiation largely through antagonizing TNF receptor-associated factor (TRAF)mediated K63-linkage polyubiquitination in osteoclast precursor cells. CYLD activity is controlled by I kappa B kinase (IKK), but the molecular mechanism(s) governing CYLD protein stability remains largely undefined. Here, we report that SCF beta-TRCP regulates the ubiquitination and degradation of CYLD, a process dependent on prior phosphorylation of CYLD at Ser432/Ser436 by IKK. Furthermore, depletion of beta-TRCP induced CYLD accumulation and TRAF6 deubiquitination in osteoclast precursor cells, leading to suppression of RANKL-induced osteoclast differentiation. Therefore, these data pinpoint the IKK/beta-TRCP/CYLD signaling pathway as an important modulator of osteoclastogenesis.
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