Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism

Wang, Yao; Li, Yong; Hu, Guanghui; Huang, Xuan; Rao, Hai; Xiong, Xiangyang; Luo, Zhijun; Lu, Quqin; Luo, Shuhong

doi:10.1016/j.cellsig.2016.06.010

Cited by 16 publications

(22 citation statements)

References 52 publications

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“…In our previous study (17), SuFu is demonstrated to be stabilized by Nek2A through phosphorylation on two specific sites of T225 and S352. In the present study, we identify a new mechanism for SuFu regulation as Nek2A impedes ubiquitin/proteasome proteolysis of SuFu.…”

Section: Discussionmentioning

confidence: 86%

“…In a previous study, we demonstrated that Nek2A is an interacting protein of SuFu and Nek2A stabilizes SuFu (17). Here we further investigated the detailed mechanism of SuFu stabilization induced by Nek2A.…”

Section: Resultsmentioning

confidence: 96%

“…Therefore, we generated Nek2A miRNAi constructs that inhibit Nek2A expression (17). In HEK293T cells, repression of Nek2A by miR-Nek2A-80, -202 or -603 resulted in elevated protein levels of Gli2 and its target Gli1, but no obvious change of Smo, which is a member of the frizzled family of seven-pass transmembrane receptors (33) (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous study (17), we employed a yeast two-hybrid approach to identify human SuFu interacting proteins. We found NIMA (never in mitosis A)-related expressed kinase 2A (Nek2A) as one of the SuFu-interacting proteins.…”

Section: Introductionmentioning

confidence: 99%

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

Zhou

Huang

et al. 2016

International Journal of Oncology

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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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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhou

Huang

et al. 2016

International Journal of Oncology

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“…Given the crucial modulatory effects of Sufu on GLI in both the cytoplasm and the nucleus, and the existence of different ubiquitin ligases responsible for GLI ubiquitination, such as Cul3-HIB/SPOP and SCF Slimb/β-TrCP , other ubiquitin ligases for Sufu ubiquitination may exist in the cytoplasm that are distinct from SCF Fbxl17 , which ubiquitinates nuclear Sufu. Additionally, our team recently identified NIMA-related expressed kinase 2A (Nek2A) as a Sufu-interacting protein by a yeast two-hybrid screen; the enzyme could phosphorylate and stabilize Sufu, consequently dampening Hh/GLI2 signalling (96,97). It is likely that different post-translational modifications, including phosphorylation and ubiquitination, are orchestrated to modulate the stability of the Sufu protein, although additional studies are required to unveil other regulations and the relationships between them.…”

Section: Regulation Of Sufu At the Mrna And Protein Levelmentioning

confidence: 99%

Molecular mechanisms of suppressor of fused in regulating the hedgehog signalling pathway (Review)

et al. 2018

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Highly conserved throughout evolution, the hedgehog (Hh) signalling pathway has been demonstrated to be involved in embryonic development, stem cell maintenance and tissue homeostasis in animals ranging from invertebrates to vertebrates. In the human body, a variety of cancer types are associated with the aberrantly activated Hh signalling pathway. Multiple studies have revealed suppressor of fused (Sufu) as a key negative regulator of this signalling pathway. In vertebrates, Sufu primarily functions as a tumor suppressor factor by interacting with and inhibiting glioma-associated oncogene homologues (GLIs), which are the terminal transcription factors of the Hh signalling pathway and belong to the Kruppel family of zinc finger proteins; by contrast, the regulation of Sufu itself remains relatively unclear. In the present review article, we focus on the effects of Sufu on the Hh signalling pathway in tumourigenesis and the molecular mechanisms underlying the regulation of GLI by Sufu. In addition, the factors modulating the activity of Sufu at post-transcriptional levels are also discussed.

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Protein modifications in Hedgehog signaling

Liu

Peng

et al. 2021

BioEssays

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The complexity of the Hedgehog (Hh) signaling cascade has increased over the course of evolution; however, it does not suffice to accommodate the dynamic yet robust requirements of differential Hh signaling activity needed for embryonic development and adult homeostatic maintenance. One solution to solve this dilemma is to apply multiple forms of post‐translational modifications (PTMs) to the core Hh signaling components, modulating their abundance, localization, and signaling activity. This review summarizes various forms of protein modifications utilized to regulate Hh signaling, with a special emphasis on crosstalk between different forms of PTMs and their feedback regulation by Hh signaling.

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Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism

Cited by 16 publications

References 52 publications

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

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

Molecular mechanisms of suppressor of fused in regulating the hedgehog signalling pathway (Review)

Protein modifications in Hedgehog signaling

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