Smurf2‐mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke

Yu, Yung Luen; Chou, Ruey Hwang; Shyu, Woei Cherng; Hsieh, Shu Ching; Wu, C.; Chiang, Shu Ya; Chang, Wei; Chen, Jia Ni; Tseng, Yen Ju; Lin, Yu Hsuan; Lee, Wei; Yeh, Su Peng; Hsu, Jennifer L.; Yang, Cheng Chieh; Hung, Shih Chieh; Hung, Mien Chie

doi:10.1002/emmm.201201783

Cited by 94 publications

(93 citation statements)

References 66 publications

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“…Consistent with a role of Stx on Pc stability in Drosophila development, proteasomal degradation has been reported to affect the stability of several PcG components in cultured vertebrate cells, including three PRC1 proteins BMI1, RING1B, and PHC, and one PRC2 protein EZH2 (Ben-Saadon et al, 2006;Maertens et al, 2010;Wu et al, 2010;Zaaroor-Regev et al, 2010;Sahasrabuddhe et al, 2011;Wu and Zhang, 2011;Yu et al, 2013). It is thus highly likely that protein degradation may play a general role in regulating PcG activity.…”

Section: Regulated Protein Degradation Plays a General Role In Modulamentioning

confidence: 84%

Stuxnet Facilitates the Degradation of Polycomb Protein during Development

Zhang

et al. 2016

Developmental Cell

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Polycomb-group (PcG) proteins function to ensure correct deployment of developmental programs by epigenetically repressing target gene expression. Despite the importance, few studies have been focused on the regulation of PcG activity itself. Here, we report a Drosophila gene, stuxnet (stx), that controls Pc protein stability. We find that heightened stx activity leads to homeotic transformation, reduced Pc activity, and de-repression of PcG targets. Conversely, stx mutants, which can be rescued by decreased Pc expression, display developmental defects resembling hyperactivation of Pc. Our biochemical analyses provide a mechanistic basis for the interaction between stx and Pc; Stx facilitates Pc degradation in the proteasome, independent of ubiquitin modification. Furthermore, this mode of regulation is conserved in vertebrates. Mouse stx promotes degradation of Cbx4, an orthologous Pc protein, in vertebrate cells and induces homeotic transformation in Drosophila. Our results highlight an evolutionarily conserved mechanism of regulated protein degradation on PcG homeostasis and epigenetic activity.

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Section: Regulated Protein Degradation Plays a General Role In Modulamentioning

confidence: 84%

Stuxnet Facilitates the Degradation of Polycomb Protein during Development

Zhang

et al. 2016

Developmental Cell

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“…Another study reported that treatment of the DNA methylation inhibitor DZNep in 293T cells upregulates the ubiquitin ligase PRAJA1, which degrades EZH2 in vitro (41). Additionally, another study indicated that the SMAD ubiquitination regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase responsible for the polyubiquitination and proteasome-mediated degradation of EZH2 in human mesenchymal stem cells (hMSCs) in vitro and in an intracranial xenograft model (42). These studies provide insights into the mechanism of EZH2 degradation through ubiquitination, mostly in normal somatic cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

Wang¹,

Peng²,

Pavlyukov³

et al. 2017

Journal of Clinical Investigation

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“…Smurf2 promotes senescence in fibroblasts, whereas in the nervous system Smurf2 may induce neuronal differentiation and promote neuronal polarization. [66][67][68] Whether sumoylation contributes to biological responses of Smurf2 besides EMT will be important to investigate in future studies.…”

Section: Discussionmentioning

confidence: 99%

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

Karve

Dadakhujaev

et al. 2015

Cell Death Differ

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Epithelial-mesenchymal transition (EMT) is a fundamental cellular process in epithelial tissue development, and can be reactivated in cancer contributing to tumor invasiveness and metastasis. The cytokine transforming growth factor-β (TGFβ) is a key inducer of EMT, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Here, we report that knockdown of the ubiquitin ligase Smurf2 promotes the ability of TGFβ to induce EMT in a three-dimensional cell culture model of NMuMG mammary epithelial cells. In other studies, we identify Smurf2 as a target of the small ubiquitin like modifier (SUMO) pathway. We find that the SUMO-E2 conjugating enzyme Ubc9 and the SUMO E3 ligase PIAS3 associate with Smurf2 and promote its sumoylation at the distinct sites of Lysines 26 and 369. The sumoylation of Smurf2 enhances its ability to induce the degradation of the TGFβ receptor and thereby suppresses EMT in NMuMG cells. Collectively, our data reveal that Smurf2 acts in a sumoylationregulated manner to suppress TGFβ-induced EMT. These findings have significant implications for our understanding of epithelial tissue development and cancer. Cell Death and Differentiation (2016) 23, 876-888; doi:10.1038/cdd.2015; published online 18 December 2015Epithelial-mesenchymal transition (EMT) is an essential process in epithelial tissue morphogenesis in the developing organism and contributes to postnatal events including mammary postnatal gland development as well as wound healing.1,2 Importantly, EMT can be reactivated during cancer and may contribute to tumor invasiveness.3 Epithelial cells undergoing EMT change phenotypically from cuboidal to fibroblastic morphology, lose epithelial markers including E-cadherin, gain mesenchymal markers, and display increased cell motility and invasiveness. 4,5 The secreted factor transforming growth factor-β (TGFβ) has emerged as a potent inducer of EMT with key roles in development and cancer.6 Thus, there has been interest in the mechanisms that mediate TGFβ-induced EMT.Smurf2 (Smad (Sma and mad) ubiquitination regulatory factor-2) is a HECT (for homology to E6 carboxy terminus domain)-containing E3 ubiquitin ligase that specifies substrates for ubiquitination and degradation by the proteasome.7,8 Smurf2 regulates key biological processes during development and homeostasis including cell polarity, cell cycle, and senescence in an E3 ligase-dependent or -independent manner.9-15 The biological functions of Smurf2 occur via regulation of signaling pathways including the TGFβ-Smad signaling pathway. [16][17][18][19][20][21][22][23] However, the role of Smurf2 in TGFβ-induced EMT has remained to be determined.Sumoylation refers to the covalent attachment of the small ubiquitin-like modifier (SUMO), to protein substrates by the SUMO pathway.24 SUMO is linked to its substrates by an iso-peptide bond between C-terminal carboxyl group of SUMO and ε-amino group of a lysine residue in the substrate. The SUMO E2 conjugating enzyme Ubc9, the second enzyme of a three-step catalytic cascade...

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Smurf2‐mediated degradation of EZH2 enhances neuron differentiation and improves functional recovery after ischaemic stroke

Cited by 94 publications

References 66 publications

Stuxnet Facilitates the Degradation of Polycomb Protein during Development

Stuxnet Facilitates the Degradation of Polycomb Protein during Development

Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2

The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner

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