Department of Cell Biology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, The Netherlands.
Mol Cell. 2010 Mar 12;37(5):607-19. doi: 10.1016/j.molcel.2010.01.035.
The mechanism by which Wnt receptors transduce signals to activate downstream beta-catenin-mediated target gene transcription remains incompletely understood but involves Frizzled (Fz) receptor-mediated plasma membrane recruitment and activation of the cytoplasmic effector Dishevelled (Dvl). Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation. Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD. At the molecular level, CYLD interacts with and regulates K63-linked ubiquitination of Dvl. Enhanced ubiquitination of the polymerization-prone DIX domain in CYLD-deficient cells positively links to the signaling activity of Dvl. Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses.
Wnt 受体将信号转导激活下游β-连环蛋白介导的靶基因转录的机制尚不完全清楚，但涉及卷曲（Fz）受体介导的质膜募集和细胞质效应物 Dvl（Dishevelled）的激活。在这里，我们鉴定出去泛素化酶 CYLD，家族性圆柱瘤肿瘤抑制基因，作为 Wnt/β-连环蛋白信号转导中近端事件的负调节剂。从培养细胞中耗尽 CYLD 可显著增强 Wnt 诱导的β-连环蛋白积累和靶基因激活。此外，我们证明了来自 CYLD 突变的人类圆柱瘤皮肤肿瘤中存在过度活跃的 Wnt 信号。在分子水平上，CYLD 与 Dvl 的 K63 连接泛素化相互作用并调节其活性。在 CYLD 缺陷细胞中，易于聚合的 DIX 结构域的增强泛素化与 Dvl 的信号活性呈正相关。总之，我们的结果表明，CYLD 的缺失通过聚合 Dvl 的 hyperubiquitination 驱动 Wnt 反应增强的机制引发人类圆柱瘤中的肿瘤生长。
