4.6 Article

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

Journal

INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 50, Issue 2, Pages 373-380

Publisher

SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2016.3819

Keywords

Nek2A; SuFu; Gli; Hedgehog signaling; feedback loop

Categories

Funding

  1. National Natural Science Foundation of China [81560457, 31460305]
  2. Natural Science Foundation of Jiangxi Province [20151BAB205037]

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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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