Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway

Zhou,Fen; Huang,Dengliang; Li,Yong; Hu,Guanghui; Rao,Hai; Lu,Quqin; Luo,Shiwen; Wang,Yao

doi:10.3892/ijo.2016.3819

Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway

Authors:
- Fen Zhou
- Dengliang Huang
- Yong Li
- Guanghui Hu
- Hai Rao
- Quqin Lu
- Shiwen Luo
- Yao Wang
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Affiliations: Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA, Department of Biostatistics and Epidemiology, School of Public Health, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: December 23, 2016 https://doi.org/10.3892/ijo.2016.3819
Pages: 373-380
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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