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

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)15-27
Number of pages13
JournalMolecular Cell
Volume28
Issue number1
DOIs
Publication statusPublished - 2007 Oct 12

Keywords

  • CELLCYCLE
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Yang, H., Minamishima, Y. A., Yan, Q., Schlisio, S., Ebert, B. L., Zhang, X., Zhang, L., Kim, W. Y., Olumi, A. F., & Kaelin, W. G. (2007). pVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2. Molecular Cell, 28(1), 15-27. https://doi.org/10.1016/j.molcel.2007.09.010