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Mol Cell. 2007 Oct 12;28(1):15-27.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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-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.

PMID:
17936701
PMCID:
PMC2128776
DOI:
10.1016/j.molcel.2007.09.010
[Indexed for MEDLINE]
Free PMC Article

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