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

Molecular cell | Oct 12, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17936701

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 RIS Download

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

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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

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