PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway

Vershinin, Zlata; Feldman, Michal; Chen, Ayelet; Levy, Dan

doi:10.1074/jbc.m115.697292

Cited by 57 publications

(58 citation statements)

References 39 publications

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“…FoxM1 methylation by SETD3 adds a new regulatory dimension to this complex process. As many non-histone proteins in the human proteome are known to be methylated2728293031323334, we hypothesize that additional cellular factors that regulate the VEGF signaling under hypoxia may also be methylated by SETD3. Interestingly, two of the known VEGF receptors35, FLT1 (VEGFR1) and KDR (VEGFR2), were identified as SETD3 interacting proteins in our ProtoArray screen (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Chromatin associated SETD3 negatively regulates VEGF expression

Cohn

Feldman

Weil

et al. 2016

Sci Rep

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SETD3 is a member of the protein lysine methyltransferase (PKMT) family, which catalyzes the addition of methyl group to lysine residues. Accumulating data suggest that PKMTs are involved in the regulation of a broad spectrum of biological processes by targeting histone and non-histone proteins. Using a proteomic approach, we have identified 172 new SETD3 interacting proteins. We show that SETD3 binds and methylates the transcription factor FoxM1, which has been previously shown to be associated with the regulation of VEGF expression. We further demonstrate that under hypoxic conditions SETD3 is down-regulated. Mechanistically, we find that under basal conditions, SETD3 and FoxM1 are enriched on the VEGF promoter. Dissociation of both SETD3 and FoxM1 from the VEGF promoter under hypoxia correlates with elevated expression of VEGF. Taken together, our data reveal a new SETD3-dependent methylation-based signaling pathway at chromatin that regulates VEGF expression under normoxic and hypoxic conditions.

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Section: Discussionmentioning

confidence: 99%

Chromatin associated SETD3 negatively regulates VEGF expression

Cohn

Feldman

Weil

et al. 2016

Sci Rep

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“…Nuclear PAK4 has been found in endometrial cancer in postmenopausal women (Siu et al 2015). Recently, PAK4 has been shown to be methylated by lysine methyltransferase SETD6; and its interaction with SETD6 and β-catenin regulates β-catenin-target genes (Vershinin et al, 2016). Another PAK-signaling-mediated regulation of gene expression is PAK1 phosphorylation-dependent modulation of corepressor functions.…”

Section: Paks Nuclear Functionsmentioning

confidence: 99%

Structure, biochemistry, and biology of PAK kinases

Kumar

Sanawar

et al. 2017

Gene

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PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs.

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“…Lysine methylation may be important not only in epigenetic regulation of gene expression, but also in the regulation of cellular signal transduction pathways (Kurash et al, 2008;Van Duyne et al, 2008;Abu-Farha et al, 2011;Herz et al, 2013;Jakobsson et al, 2015;Zhang et al, 2015;Vershinin et al, 2016). During E. histolytica phagocytosis, an event related to its pathogenicity (Orozco et al, 1983), EhHKMT2 and EhHKMT4 were located around ingested erythrocytes and they colocalized and co-immunoprecipitated with EhADH, a protein involved in phagocytosis (Rodriguez et al, 1989;Garcia-Rivera et al, 1999), suggesting that these EhHKMTs could methylate some proteins that are implicated in this process.…”

Section: Discussionmentioning

confidence: 99%

“…These modifications are catalyzed by lysine methyltransferases (HKMTs); and most of them contain a SET domain (Dillon et al, 2005), which was originally identified in Drosophila suppressor of variegation [Su(var)3-9] (Tschiersch et al, 1994), enhancer of zeste [E(z)] (Jones and Gelbart, 1993) and trithorax (Stassen et al, 1995). In addition to histones, HKMTs also target a broad range of other cellular proteins, suggesting that they contribute to the regulation of additional processes (Kurash et al, 2008;Van Duyne et al, 2008;Abu-Farha et al, 2011;Jakobsson et al, 2015;Zhang et al, 2015;Vershinin et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Identification and functional characterization of lysine methyltransferases of Entamoeba histolytica

Borbolla-Vázquez

Orozco

Medina-Gómez

et al. 2016

Molecular Microbiology

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Lysine methylation of histones, a posttranslational modification catalyzed by lysine methyltransferases (HKMTs), plays an important role in the epigenetic regulation of transcription. Lysine methylation of non-histone proteins also impacts the biological function of proteins. Previously it has been shown that lysine methylation of histones of Entamoeba histolytica, the protozoan parasite that infects 50 million people worldwide each year and causing up to 100,000 deaths annually, is implicated in the epigenetic machinery of this microorganism. However, the identification and characterization of HKMTs in this parasite had not yet been determined. In this work we identified four HKMTs in E. histolytica (EhHKMT1 to EhHKMT4) that are expressed by trophozoites. Enzymatic assays indicated that all of them are able to transfer methyl groups to commercial histones. EhHKMT1, EhHKMT2 and EhHKMT4 were detected in nucleus and cytoplasm of trophozoites. In addition EhHKMT2 and EhHKMT4 were located in vesicles containing ingested cells during phagocytosis, and they co-immunoprecipitated with EhADH, a protein involved in the phagocytosis of this parasite. Results suggest that E. histolytica uses its HKMTs to regulate transcription by epigenetic mechanisms, and at least two of them could also be implicated in methylation of proteins that participate in phagocytosis.

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PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway

Cited by 57 publications

References 39 publications

Chromatin associated SETD3 negatively regulates VEGF expression

Chromatin associated SETD3 negatively regulates VEGF expression

Structure, biochemistry, and biology of PAK kinases

Identification and functional characterization of lysine methyltransferases of Entamoeba histolytica

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