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SCF?-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.


ABSTRACT: CYLD negatively regulates the NF-?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?B kinase (IKK), but the molecular mechanism(s) governing CYLD protein stability remains largely undefined. Here, we report that SCF?-TRCP regulates the ubiquitination and degradation of CYLD, a process dependent on prior phosphorylation of CYLD at Ser432/Ser436 by IKK. Furthermore, depletion of ?-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/?-TRCP/CYLD signaling pathway as an important modulator of osteoclastogenesis.

SUBMITTER: Wu X 

PROVIDER: S-EPMC4147317 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination.

Wu Xiaomian X   Fukushima Hidefumi H   North Brian J BJ   Nagaoka Yoshiyuki Y   Nagashima Katsuyuki K   Deng Feng F   Okabe Koji K   Inuzuka Hiroyuki H   Wei Wenyi W  

Oncotarget 20140601 12


CYLD negatively regulates the NF-κB 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 IκB kinase (IKK), but the molecular mechanism(s) governing CYLD protein stability remains largely undefined. Here, we report that SCFβ-TRCP regulates the ubiquitination and degradation of CYLD, a process dependent on prior phosphorylation of CYLD  ...[more]

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