pVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2

Haifeng Yang, Yoji Andrew Minamishima, Qin Yan, Susanne Schlisio, Benjamin L. Ebert, Xiaoping Zhang, Liang Zhang, William Y. Kim, Aria F. Olumi, William G. Kaelin

研究成果: Article査読

134 被引用数 (Scopus)

抄録

The VHL tumor suppressor protein (pVHL) is part of an E3 ubiquitin ligase that targets HIF for destruction. pVHL-defective renal carcinoma cells exhibit increased NF-κB activity but the mechanism is unclear. NF-κB affects tumorigenesis and therapeutic resistance in some settings. We found that pVHL associates with the NF-κB agonist Card9 but does not target Card9 for destruction. Instead, pVHL serves as an adaptor that promotes the phosphorylation of the Card9 C terminus by CK2. Elimination of these sites markedly enhanced Card9's ability to activate NF-κB in VHL+/+ cells, and Card9 siRNA normalized NF-κB activity in VHL-/- cells and restored their sensitivity to cytokine-induced apoptosis. Furthermore, downregulation of Card9 in VHL-/- cancer cells reduced their tumorigenic potential. Therefore pVHL can serve as an adaptor for both a ubiquitin conjugating enzyme and a kinase. The latter activity, which promotes Card9 phosphorylation, links pVHL to control of NF-κB activity and tumorigenesis.

本文言語English
ページ(範囲)15-27
ページ数13
ジャーナルMolecular Cell
28
1
DOI
出版ステータスPublished - 2007 10 12

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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