title: GABARAPL1 negatively regulates Wnt/β-catenin signaling by mediating Dvl2 degradation through the autophagy pathway.
abstract: Wnt signaling is critical for many biological processes and is tightly regulated. In this study, we found that GABARAPL1 (GABA(A) receptor-associated protein like 1, GABARAPL1) interacts with Dvl2 by both yeast two-hybrid screening and immunoprecipitation experiments. Furthermore, we observed that p62 is required for the interaction of Dvl2 and GABARAPL1. Luciferase assays indicated that GABARAPL1 represses Wnt/β-catenin signaling stimulated by Wnt1, Dvl2 and β-catenin. We further demonstrated that GABARAPL1 mediates degradation of Dvl2 and the effect is blocked by addition of 3-MA, a specific inhibitor of autophagy. Finally, we provided evidence that over-expression of GABARAPL1 inhibits proliferation and tumor growth of MCF7 cells in vitro and in nude mice. Taken together, our results suggested that GABARAPL1 as a tumor repressor inhibits Wnt signaling via mediating Dvl2 degradation through the autophagy pathway.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing, R.P. China.
authors.forename: Yanquan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Yinyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Wang
authors.forename: Fangli
authors.initials: F
authors.lastname: Ren
authors.forename: Yonggong
authors.initials: Y
authors.lastname: Zhai
authors.forename: Dianjun
authors.initials: D
authors.lastname: Wang
authors.forename: Baoqing
authors.initials: B
authors.lastname: Jia
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Xia
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003001:Cloning, Molecular; D000072261:Dishevelled Proteins; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids; D011485:Protein Binding; D015398:Signal Transduction; D014162:Transfection; D020798:Two-Hybrid System Techniques; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology; D051155:Wnt1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C000606582:Dvl2 protein, mouse; C480859:Gabarapl1 protein, mouse; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins; C495247:WNT1 protein, human; D051155:Wnt1 Protein; D051176:beta Catenin; D008156:Luciferases