title: Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway.
abstract: Suppressor of Fused (SuFu), one of the most conserved components of the Hedgehog (Hh) signaling, binds Gli transcription factors and impedes activation of target gene expression in mammalian cells. Despite the central importance of SuFu in the Hh pathway, little is known about SuFu regulation. In a previous study, we identified NIMA-related expressed kinase 2A (Nek2A) as a SuFu-interacting protein. Here, we show that Nek2A stabilizes SuFu through impairing ubiquitin/proteasome degradation of SuFu. In addition, Nek2A negatively regulates target genes of Hh signaling as well as Gli2 transcriptional activity. In turn, inhibition of Hh signaling by GANT61 diminishes mRNA and protein levels of Nek2A, and Hh agonist promotes transcription of NEK2A gene. Chromatin immunoprecipitation assays revealed that Gli1 and Gli2 directly bind to the promoter regions of NEK2A gene and induced its transcription. Thus, we uncovered one of the mechanisms by which Nek2A acts as a modulator of the Hh signaling pathway in the context of a novel negative-feedback loop, which may offer new insights into Gli-mediated Hh signaling regulation in development and human diseases.
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Dengliang
authors.initials: D
authors.lastname: Huang
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Rao
authors.affiliation: Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Quqin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Shiwen
authors.initials: S
authors.lastname: Luo
authors.affiliation: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
mesh_terms: D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D000072379:NIMA-Related Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D012097:Repressor Proteins; C490764:SUFU protein, human; D000071676:Zinc Finger Protein GLI1; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases