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.
Yang
Haifeng
H
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Minamishima
Yoji Andrew
YA
Yan
Qin
Q
Schlisio
Susanne
S
Ebert
Benjamin L
BL
Zhang
Xiaoping
X
Zhang
Liang
L
Kim
William Y
WY
Olumi
Aria F
AF
Kaelin
William G
WG
D000595:Amino Acid Sequence; D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms; D008099:Liver / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009368:Neoplasm Transplantation; D016716:PC12 Cells; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
D053468:CARD Signaling Adaptor Proteins; C505855:CARD9 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D047390:Casein Kinase II; C497446:VHL protein, human