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pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2.

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-kappaB activity but the mechanism is unclear. NF-kappaB affects tumorigenesis and therapeutic resistance in some settings. We found that pVHL associates with the NF-kappaB 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-kappaB in VHL(+/+) cells, and Card9 siRNA normalized NF-kappaB 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-kappaB activity and tumorigenesis.

Pubmed ID: 17936701


  • Yang H
  • Minamishima YA
  • Yan Q
  • Schlisio S
  • Ebert BL
  • Zhang X
  • Zhang L
  • Kim WY
  • Olumi AF
  • Kaelin WG


Molecular cell

Publication Data

October 12, 2007

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA068490
  • Agency: NCI NIH HHS, Id: R01 CA068490-06
  • Agency: NCI NIH HHS, Id: R01 CA068490-07
  • Agency: NCI NIH HHS, Id: R01 CA068490-08
  • Agency: NCI NIH HHS, Id: R01 CA068490-09
  • Agency: NCI NIH HHS, Id: R01 CA068490-10
  • Agency: NCI NIH HHS, Id: R01 CA068490-11A1
  • Agency: NCI NIH HHS, Id: R01 CA068490-12
  • Agency: NCI NIH HHS, Id: T32 CA009172

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • CARD Signaling Adaptor Proteins
  • Carcinoma, Renal Cell
  • Casein Kinase II
  • HeLa Cells
  • Humans
  • Kidney Neoplasms
  • Liver
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • NF-kappa B
  • Neoplasm Transplantation
  • PC12 Cells
  • Phosphorylation
  • RNA, Small Interfering
  • Rats
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
  • Von Hippel-Lindau Tumor Suppressor Protein