title: Ubiquitin-Specific Protease 4 Antagonizes Osteoblast Differentiation Through Dishevelled.
abstract: The canonical Wnt/β-catenin signaling pathway plays a pivotal role and is essentially required for the osteoblast differentiation and bone formation. In this study, we found ubiquitin-specific peptidase 4 (USP4) to strongly inhibit the Wnt/β-catenin signaling by removing Lysine-63 linked poly-ubiquitin chain from Dishevelled (Dvl). Ectopic expression of USP4 promoted β-catenin poly-ubiquitination and thus inhibited Wnt-induced accumulation of cytosolic β-catenin and counteracted Wnt-induced transcriptional activity. Moreover, USP4 knockdown or USP4 knockout led to an increase in the active β-catenin levels and in activation of Wnt/β-catenin-induced transcription. Functional studies in C2C12 myoblasts and KS483 osteoprogenitor cells showed that ectopic expression of USP4 resulted in impaired activation of endogenous Wnt3a-induced genes and decreased osteoblast differentiation and mineralization, whereas USP4 depletion showed the opposite effect. These results identify USP4 as a novel regulator of Dvl in Wnt/β-catenin signal and show its involvement in Wnt3a-induced osteoblast differentiation. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China. zhoufangfang@suda.edu.cn.|Institutes of Biology and Medical Science, Soochow University, Suzhou, PR China. zhoufangfang@suda.edu.cn.|Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands. zhoufangfang@suda.edu.cn.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Fang
authors.affiliation: Institutes of Biology and Medical Science, Soochow University, Suzhou, PR China.
authors.forename: Tong
authors.initials: T
authors.lastname: Dai
authors.affiliation: Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Jia
authors.affiliation: State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Hangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, China. L_Zhang@zju.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
mesh_terms: D002454:Cell Differentiation / Q000502:physiology*; D000072261:Dishevelled Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010006:Osteoblasts / Q000378:metabolism*; D025821:Polyubiquitin / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; C486203:USP4 protein, human; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D025821:Polyubiquitin; D064570:Ubiquitin-Specific Proteases
keywords: DISHEVELLED; OSTEOBLAST DIFFERENTIATION; UBIQUITINATION; USP4; Wnt3a; β-CATENIN