pVHL作为衔接蛋白，促进CK2对NF-κB激动剂Card9的抑制性磷酸化。
pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2.
作者信息
Yang Haifeng, Minamishima Yoji Andrew, Yan Qin, Schlisio Susanne, Ebert Benjamin L, Zhang Xiaoping, Zhang Liang, Kim William Y, Olumi Aria F, Kaelin William G
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Mol Cell. 2007 Oct 12;28(1):15-27. doi: 10.1016/j.molcel.2007.09.010.
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.
VHL肿瘤抑制蛋白（pVHL）是一种E3泛素连接酶的一部分，该连接酶将缺氧诱导因子（HIF）作为降解靶点。pVHL缺陷型肾癌细胞表现出增强的核因子κB（NF-κB）活性，但其机制尚不清楚。在某些情况下，NF-κB会影响肿瘤发生和治疗抗性。我们发现pVHL与NF-κB激动剂Card9相互作用，但不会将Card9作为降解靶点。相反，pVHL充当衔接蛋白，促进CK2对Card9 C末端的磷酸化。消除这些位点显著增强了Card9在VHL（+/+）细胞中激活NF-κB的能力，并且Card9小干扰RNA（siRNA）使VHL（-/-）细胞中的NF-κB活性恢复正常，并恢复了它们对细胞因子诱导的细胞凋亡的敏感性。此外，VHL（-/-）癌细胞中Card9的下调降低了它们的致瘤潜力。因此，pVHL可以作为泛素结合酶和激酶的衔接蛋白。促进Card9磷酸化的后一种活性将pVHL与NF-κB活性的控制和肿瘤发生联系起来。
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