Department of Molecular Cell Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan.
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, 113-0032, Japan.
Commun Biol. 2020 Nov 12;3(1):666. doi: 10.1038/s42003-020-01386-2.
β-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.
β-连环蛋白是 Wnt 信号通路的重要组成部分。由于该通路的失调或突变会导致许多疾病，包括癌症，因此β-连环蛋白的水平由 Wnt 信号通路中的破坏复合物仔细调节。然而，β-连环蛋白泛素化和降解的调节机制尚不清楚。在这里，我们发现 WNK（无赖氨酸[K]）激酶是 Wnt 信号通路的潜在调节剂。我们表明，WNK 保护β-连环蛋白与 Glucose-Induced degradation Deficient（GID）复合物之间的相互作用，GID 复合物包括针对β-连环蛋白的 E3 泛素连接酶，并且 WNK 调节β-连环蛋白的水平。此外，我们表明 WNK 抑制剂诱导β-连环蛋白降解，其中一种抑制剂抑制了小鼠的异种移植物肿瘤发展。这些结果表明，WNK 是β-连环蛋白的一个以前未被识别的调节剂，也是癌症的治疗靶点。
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