Phosphomevalonate Kinase Controls β-Catenin Signaling via the Metabolite 5-Diphosphomevalonate
Phosphomevalonate Kinase Controls β-Catenin Signaling via the Metabolite 5-Diphosphomevalonate
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DOI：
10.1002/advs.202204909
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发表时间：
2023
期刊：
影响因子：
15.1
通讯作者：
Youjun Li
中科院分区：
文献类型：
--
作者：
Zhiqiang Chen;Xinyi Zhou;Xiaojun Zhou;Yi Tang;Mingzhu Lu;Jianhong Zhao;Chenhui Tian;Mingzhi Wu;Yanliang Liu;Edward V Prochownik;Fubing Wang;Youjun Li
Beta-catenin signaling is abnormally activated in cancer. Here, this work screens.the mevalonate metabolic pathway enzyme PMVK to stabilize -catenin.signaling using a human genome-wide library. On the one hand,.PMVK-produced MVA-5PP competitively binds to CKI to prevent -catenin.Ser45 phosphorylation and degradation. On the other hand, PMVK functions.as a protein kinase to directly phosphorylate -catenin Ser184 to increase its.protein nuclear localization. This synergistic effect of PMVK and MVA-5PP.together promotes -catenin signaling. In addition, PMVK deletion impairs.mouse embryonic development and causes embryonic lethal. PMVK.deficiency in liver tissue alleviates DEN/CCl4-induced hepatocarcinogenesis..Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and.PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings.reveal a non-canonical function of a key metabolic enzyme PMVK and a novel.link between the mevalonate pathway and -catenin signaling in.carcinogenesis providing a new target for clinical cancer therapy.
