单位：[1]The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China四川省人民医院[2]Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China[3]Department of Orthopedics,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China外科学系华中科技大学同济医学院附属同济医院骨科[4]College of Life and Health Science, Northeastern University, Shenyang, China[5]Verve Therapeutics, Cambridge, MA, USA[6]Department of Neurology, Harvard Medical School, The F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA[7]Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China四川省人民医院
The membrane-tethered protease Tiki antagonizes Wnt3a signaling by cleaving and inactivating Wnt3a in Wnt-producing cells. Tiki also functions in Wnt-receiving cells to antagonize Wnt signaling by an unknown mechanism. Here, we demonstrate that Tiki inhibition of Wnt signaling at the cell surface requires Frizzled (FZD) receptors. Tiki associates with the Wnt-FZD complex and cleaves the N-terminus of Wnt3a or Wnt5a, preventing the Wnt-FZD complex from recruiting and activating the coreceptor LRP6 or ROR1/2 without affecting Wnt-FZD complex stability. Intriguingly, we demonstrate that the N-terminus of Wnt3a is required for Wnt3a binding to LRP6 and activating beta-catenin signaling, while the N-terminus of Wnt5a is dispensable for recruiting and phosphorylating ROR1/2. Both Tiki enzymatic activity and its association with the Wnt-FZD complex contribute to its inhibitory function on Wnt5a. Our study uncovers the mechanism by which Tiki antagonizes Wnt signaling at the cell surface and reveals a negative role of FZDs in Wnt signaling by acting as Tiki cofactors. Our findings also reveal an unexpected role of the Wnt3a N-terminus in the engagement of the coreceptor LRP6.
基金：
National Natural Science Foundation of China [81870620]; Fundamental Research Funds for the Central Universities, HUST [2021GCRC033]; Sichuan Provincial People's Hospital; National Institutes of Health [R01GM57603, R35GM134953/MIRA]
第一作者单位：[1]The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China[2]Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
共同第一作者：
通讯作者：
通讯机构：[1]The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China[2]Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China[7]Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, China
推荐引用方式(GB/T 7714)：
Li Mingyi,Zheng Jing,Luo Dong,et al.Frizzled receptors facilitate Tiki inhibition of Wnt signaling at the cell surface[J].EMBO REPORTS.2023,24(6):doi:10.15252/embr.202255873.
APA：
Li, Mingyi,Zheng, Jing,Luo, Dong,Xu, Kai,Sheng, Ren...&Zhang, Xinjun.(2023).Frizzled receptors facilitate Tiki inhibition of Wnt signaling at the cell surface.EMBO REPORTS,24,(6)
MLA：
Li, Mingyi,et al."Frizzled receptors facilitate Tiki inhibition of Wnt signaling at the cell surface".EMBO REPORTS 24..6(2023)
生物学