Emerging roles of lysine methylation on non-histone proteins

Zhang, Xi; Huang, Yaling; Shi, Xiaobing

doi:10.1007/s00018-015-2001-4

Cited by 125 publications

(110 citation statements)

References 151 publications

(200 reference statements)

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…2A; Supplemental Table S1). Relative to other KMTs, SMYD2 is recognized to have robust in vitro activity and methylate several substrates, including H3K36 (Zhang et al 2015); however, in our analysis, we did not observe physiologically relevant methylation at H3K36 by SMYD2 (N Reynoird and O Gozani, unpubl.). We identified only HSP90 among the previously known targets in our list of 159 candidate hits.…”

Section: Smyd2 Monomethylates Mapkapk3 At Lys355contrasting

confidence: 71%

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

et al. 2016

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a lethal form of cancer with few therapeutic options. We found that levels of the lysine methyltransferase SMYD2 (SET and MYND domain 2) are elevated in PDAC and that genetic and pharmacological inhibition of SMYD2 restricts PDAC growth. We further identified the stress response kinase MAPKAPK3 (MK3) as a new physiologic substrate of SMYD2 in PDAC cells. Inhibition of MAPKAPK3 impedes PDAC growth, identifying a potential new kinase target in PDAC. Finally, we show that inhibition of SMYD2 cooperates with standard chemotherapy to treat PDAC cells and tumors. These findings uncover a pivotal role for SMYD2 in promoting pancreatic cancer.

show abstract

Section: Smyd2 Monomethylates Mapkapk3 At Lys355contrasting

confidence: 71%

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

et al. 2016

View full text Add to dashboard Cite

show abstract

“…With the presence of large number of lysine methyltransferases (KMTs) in mammalian genomes (4,5), it is not surprising that an increasingly larger number of non-histone chromosomal, nuclear and cytoplasmic proteins have been found to be lysine methylated (6)(7)(8)(9). Lysine methylation can be dynamically removed by the action of demethylases (10,11), making it a feasible mechanism for signal transduction.…”

mentioning

confidence: 99%

The lysine methyltransferase SMYD2 methylates the kinase domain of type II receptor BMPR2 and stimulates bone morphogenetic protein signaling

Gao

Wang

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Lysine methylation of chromosomal and nuclear proteins is a well-known mechanism of epigenetic regulation, but relatively little is known about the role of this protein modification in signal transduction. Using an RNAi-based functional screening of the SMYD family of lysine methyltransferases (KMTs), we identified SMYD2 as a KMT essential for robust bone morphogenic protein (BMP)-but not TGFβ-induced target gene expression in HaCaT keratinocyte cells. A role for SMYD2 in BMP-induced gene expression was confirmed by shRNA knockdown and CRISPR/Cas9-mediated knockout of SMYD2. We further demonstrate that SMYD2 knockdown or knockout impairs BMPinduced phosphorylation of the signaltransducing protein SMAD1/5 and SMAD1/5 nuclear localization and interaction with SMAD4. The SMYD2 KMT activity was required to facilitate BMP-mediated signal transduction, as treatment with the SMYD2 inhibitor AZ505 suppressed BMP2-induced SMAD1/5 phosphorylation. Furthermore, we present evidence that SMYD2 likely modulates the BMP response through its function in the cytosol. We show that, although SMYD2 interacted with multiple components in the BMP pathway, it specifically methylated the kinase domain of BMP type II receptor BMPR2. Taken together, our findings suggest that SMYD2 may promote BMP signaling by directly methylating BMPR2, which, in turn, stimulates BMPR2 kinase activity and activation of the BMP pathway.Lysine methylation has been extensively studied in the context of histone proteins as a mechanism of epigenetic regulation (1-3). With the presence of large number of lysine methyltransferases (KMTs) in mammalian genomes (4,5), it is not surprising that an increasingly larger number of non-histone chromosomal, nuclear and cytoplasmic proteins have been found to be lysine methylated (6-9). Lysine methylation can be dynamically removed by the action of demethylases (10,11), making it a feasible mechanism for signal transduction. However, up to now lysine methylation has been shown to regulate signaling proteins only in a limited cases. For instances, methylation of MAP3K2 by SMYD3 has been shown to increase MAP kinase signaling and promotes the formation of Ras-driven carcinomas (12), whereas methylation of VEGFR1 by SMYD3 activates its kinase activity (13), indicating that lysine methylation can play important roles in regulation of signal transduction.TGF-β/BMP superfamily of cytokines play pleiotropic roles in embryonic development, differentiation, organ morphogenesis and tissue homeostasis (14,15). These cytokines bind the cell surface type I and type II receptors that are also serine-threonine kinases (16,17). Upon ligand binding, the type II receptor activates the type I receptor by phosphorylating the GS motif of type I receptor (18). The activated type I receptor in turn phosphorylates regulatory SMADs (R-SMADs) at the C-terminal SSXS motif. This phosphorylation disrupts inhibitory intramolecular interaction between MH2 and MH1 domains of R-SMADs and stimulates R-SMADs to form a heteromeric complex with the C...

show abstract

“…Analyzing phenotypes in single or double mutants is therefore complicated by genetic compensation. Second, enzymes that catalyze histone PTMs often have numerous nonhistone substrates, confounding analysis of the biological contribution of a given PTM (Huang and Berger 2008;Sims and Reinberg 2008;Biggar and Li 2014;Zhang et al 2015). For example, the fission yeast H3K9 methyltransferase Clr4 modifies the nonhistone substrate Mlo3 to facilitate centromeric siRNA production, a process linked to heterochromatin formation (Gerace et al 2010;Zhang et al 2011).…”

mentioning

confidence: 99%

Direct interrogation of the role of H3K9 in metazoan heterochromatin function

et al. 2016

View full text Add to dashboard Cite

A defining feature of heterochromatin is methylation of Lys9 of histone H3 (H3K9me), a binding site for heterochromatin protein 1 (HP1). Although H3K9 methyltransferases and HP1 are necessary for proper heterochromatin structure, the specific contribution of H3K9 to heterochromatin function and animal development is unknown. Using our recently developed platform to engineer histone genes in Drosophila, we generated H3K9R mutant flies, separating the functions of H3K9 and nonhistone substrates of H3K9 methyltransferases. Nucleosome occupancy and HP1a binding at pericentromeric heterochromatin are markedly decreased in H3K9R mutants. Despite these changes in chromosome architecture, a small percentage of H3K9R mutants complete development. Consistent with this result, expression of most protein-coding genes, including those within heterochromatin, is similar between H3K9R and controls. In contrast, H3K9R mutants exhibit increased open chromatin and transcription from piRNA clusters and transposons, resulting in transposon mobilization. Hence, transposon silencing is a major developmental function of H3K9.

show abstract

Emerging roles of lysine methylation on non-histone proteins

Cited by 125 publications

References 151 publications

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

The lysine methyltransferase SMYD2 methylates the kinase domain of type II receptor BMPR2 and stimulates bone morphogenetic protein signaling

Direct interrogation of the role of H3K9 in metazoan heterochromatin function

Contact Info

Product

Resources

About