Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA.
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37240, USA.
Cell Rep. 2019 Jul 23;28(4):1074-1089.e5. doi: 10.1016/j.celrep.2019.06.083.
The WNT signaling network is comprised of multiple receptors that relay various input signals via distinct transduction pathways to execute multiple complex and context-specific output processes. Integrity of the WNT signaling network relies on proper specification between canonical and noncanonical pathways, which presents a regulatory challenge given that several signal transducing elements are shared between pathways. Here, we report that USP9X, a deubiquitylase, and WWP1, an E3 ubiquitin ligase, regulate a ubiquitin rheostat on DVL2, a WNT signaling protein. Our findings indicate that USP9X-mediated deubiquitylation of DVL2 is required for canonical WNT activation, while increased DVL2 ubiquitylation is associated with localization to actin-rich projections and activation of the planar cell polarity (PCP) pathway. We propose that a WWP1-USP9X axis regulates a ubiquitin rheostat on DVL2 that specifies its participation in either canonical WNT or WNT-PCP pathways. These findings have important implications for therapeutic targeting of USP9X in human cancer.
WNT 信号网络由多个受体组成，这些受体通过不同的转导途径传递各种输入信号，以执行多种复杂且特定于上下文的输出过程。WNT 信号网络的完整性依赖于规范途径和非规范途径之间的正确规范，这是一个具有挑战性的调节问题，因为几条信号转导元件在途径之间是共享的。在这里，我们报告说，去泛素化酶 USP9X 和 E3 泛素连接酶 WWP1 调节 DVL2（一种 WNT 信号蛋白）上的泛素变阻器。我们的发现表明，USP9X 介导的 DVL2 去泛素化对于规范的 WNT 激活是必需的，而 DVL2 泛素化的增加与肌动蛋白丰富的突起定位和平面细胞极性 (PCP) 途径的激活有关。我们提出，WWP1-USP9X 轴调节 DVL2 上的泛素变阻器，指定其参与规范的 WNT 或 WNT-PCP 途径。这些发现对人类癌症中 USP9X 的治疗靶向具有重要意义。
