Affinage

SMYD2

N-lysine methyltransferase SMYD2 · UniProt Q9NRG4

Length
433 aa
Mass
49.7 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMYD2 is a SET/MYND-domain lysine methyltransferase that monomethylates a broad repertoire of histone and non-histone substrates to control transcription, cell-cycle progression, signaling, and cytoskeletal organization (PMID:17108971, PMID:26750096, PMID:31612581). Substrate recognition occurs within a peptide-binding groove formed between the catalytic SET domain and a TPR-like C-terminal domain (CTD); the CTD enforces an autoinhibited conformation that opens upon cofactor binding, and a TPR/EDEE motif within it dictates substrate specificity, with target peptides bound in a U-shaped conformation whose specificity is set largely by residues C-terminal to the target lysine (PMID:21782458, PMID:21738746, PMID:21880715, PMID:24594358, PMID:31612581). On chromatin, SMYD2 deposits repressive or activating marks in a locus-specific manner—H3K36 dimethylation with the Sin3A deacetylase complex and at TNF/IL6 promoters to suppress inflammation, H4K20me1 to recruit the compacting reader L3MBTL1 (including at the latent HIV-1 promoter), and H3K4 methylation at myocardin-bound SMC contractile gene promoters—consistent with predominantly cytoplasmic localization and minimal impact on bulk histone methylation (PMID:16805913, PMID:25825497, PMID:25583990, PMID:28494238, PMID:37615725). Its dominant role is methylation of non-histone proteins with diverse outcomes: it represses p53 (K370) and ERα (K266) and PPARγ, antagonizing competing acetylation/methylation marks, while methylation of RB (K810/K860) recruits L3MBTL1 and promotes RB phosphorylation and E2F-driven G1/S transit (PMID:17108971, PMID:20870719, PMID:22787429, PMID:24101509, PMID:38770649). SMYD2 also methylates signaling and stability determinants—PTEN (K313) and ALK to activate AKT, PARP1 (K528), BMPR2 to drive SMAD1/5 signaling, β-catenin (K133) for nuclear import, EZH2 (K307), TRAF2, c-Myc and AR to block their ubiquitin-dependent degradation, and BCAR3 (K334me1) to recruit FMNL proteins and promote migration—several of these driving cancer proliferation, metastasis, and therapy resistance (PMID:24726141, PMID:25925379, PMID:28588028, PMID:28915556, PMID:28370702, PMID:31693890, PMID:34841684, PMID:36611819, PMID:38296970, PMID:38243079). In striated muscle, SMYD2-methylated HSP90 forms a protective complex with the titin N2A domain, and oxidative glutathionylation of SMYD2 at Cys13 disrupts this complex to destabilize sarcomeres (PMID:22028380, PMID:22241783, PMID:23047121, PMID:30337525, PMID:30190324). SMYD2 activity is amplified by CDK4/6 phosphorylation and limited by STUB1-mediated proteasomal degradation (PMID:33127671, PMID:35939202).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2006 High

    Established SMYD2 as both a histone methyltransferase and a p53 regulator, defining its dual chromatin and non-histone roles from the outset.

    Evidence In vitro methyltransferase assays, Co-IP, and reporter/apoptosis assays showing p53 K370 monomethylation and H3K36me2 with Sin3A association

    PMID:16805913 PMID:17108971

    Open questions at the time
    • Genome-wide H3K36 targets not mapped
    • Physiological balance between histone and p53 activity unclear
  2. 2007 Medium

    Showed SMYD2 catalytic output is modulated by partner binding, foreshadowing chaperone-coupled regulation of its activity and specificity.

    Evidence IP-MS, domain-mapping Co-IP, and in vitro methyltransferase assays mapping HSP90α, EBP41L3, and p53 to distinct domains

    PMID:18065756

    Open questions at the time
    • Mechanism by which HSP90 shifts specificity to H3K4 unresolved
    • In vivo relevance of the HSP90 effect not tested
  3. 2010 High

    Connected SMYD2 methylation to reader-based repression and cell-cycle control by showing RB K860 methylation recruits L3MBTL1.

    Evidence In vitro methyltransferase assay, MS site mapping, and L3MBTL1 methyl-binding domain pulldowns

    PMID:20870719

    Open questions at the time
    • Genomic loci of RB-L3MBTL1 effects not defined
    • Relationship to RB phosphorylation not yet integrated
  4. 2011 High

    Defined the structural basis for SMYD2 substrate recognition and autoinhibition, explaining how a single enzyme accommodates diverse substrates and how it can be inhibited.

    Evidence Crystal structures of SMYD2 with p53 peptide, AZ505, SAH/sinefungin, plus CTD/EDEE mutagenesis with functional assays

    PMID:21738746 PMID:21782458 PMID:21880715

    Open questions at the time
    • Conformational dynamics in solution not directly observed
    • Structural basis for non-p53 substrate selection still limited
  5. 2012 High

    Revealed a cytoplasmic, muscle-specific role linking SMYD2-HSP90 methylation to titin stability and contractile function, distinct from chromatin activity.

    Evidence In vitro methyltransferase assays, HSP90 MS site mapping (K209/K615), Co-IP of Smyd2-Hsp90-titin N2A, and zebrafish knockdown muscle/cardiac phenotypes

    PMID:22028380 PMID:22241783 PMID:23047121

    Open questions at the time
    • Whether HSP90 methylation is strictly required for titin protection not isolated genetically
    • Mammalian in vivo confirmation limited
  6. 2012 High

    Showed SMYD2 methylation can be activating by demonstrating RB K810 methylation enhances RB phosphorylation and E2F-driven proliferation, establishing methylation-phosphorylation crosstalk.

    Evidence In vitro/in vivo methylation and phosphorylation assays, LC-MS/MS, E2F reporter, and cell-cycle analysis

    PMID:22787429

    Open questions at the time
    • Mechanism by which K810 methylation promotes adjacent phosphorylation unclear
  7. 2013 High

    Extended SMYD2 to nuclear hormone receptor control, showing ERα K266 methylation represses estrogen signaling and competes with p300/CBP acetylation.

    Evidence In vitro methyltransferase assay, ChIP, and gene expression analysis in MCF7 cells

    PMID:24101509

    Open questions at the time
    • Demethylase reversing K266me not identified
    • In vivo endocrine relevance not tested
  8. 2014 High

    Structurally and biochemically expanded the substrate landscape and chaperone coupling, defining how distinct substrates bind and how HSP90/P23 motifs promote methylation.

    Evidence Crystal structure of SMYD2-ERα peptide, HSP90AB1 K531/K574 MS mapping, PARP1 K528 mapping with PAR assay, and reconstituted MPXL-motif/ERα methylation

    PMID:24594358 PMID:24726141 PMID:24880080 PMID:30190324

    Open questions at the time
    • Quantitative contribution of chaperone scaffolding in cells unresolved
    • Functional consequences of HSP90 dimerization-site methylation incompletely defined
  9. 2015 High

    Cemented the dominant non-histone, cytoplasmic identity of SMYD2 and linked it to oncogenic AKT signaling via PTEN K313 methylation.

    Evidence Subcellular fractionation, SILAC proteomics with LLY-507, plus PTEN K313 methylation/mutagenesis and AKT phosphorylation assays

    PMID:25583990 PMID:25825497 PMID:25925379

    Open questions at the time
    • The small histone subset SMYD2 targets at specific loci not enumerated
    • PTEN demethylation/turnover not addressed
  10. 2016 High

    Systematically defined the cellular SMYD2 substrate space, demonstrating broad Kme1 substrate diversity beyond canonical targets.

    Evidence SILAC Kme1 immunoaffinity proteomics with shRNA and LLY-507 orthogonal validation; identification of BTF3, PDAP1, AHNAK/AHNAK2 sites; plus cell-based IP validation of additional substrates with BAY-598

    PMID:26750096 PMID:27163177

    Open questions at the time
    • Functional consequences of most newly identified sites untested
    • Site stoichiometry in vivo unknown
  11. 2017 Medium

    Broadened SMYD2 into receptor kinase, Wnt, inflammatory, and chromatin-compaction pathways, showing context-dependent activating and repressive outcomes.

    Evidence In vitro methyltransferase assays and functional readouts for BMPR2/SMAD1-5, ALK/AKT, β-catenin K133 nuclear import, STAT3/NF-κB feedback loops in Pkd1 models, and H4K20me1/L3MBTL1 at the latent HIV-1 promoter

    PMID:28370702 PMID:28494238 PMID:28588028 PMID:28604386 PMID:28915556

    Open questions at the time
    • Direct kinase-domain methylation sites on receptors not always mapped
    • Single-lab findings for several pathways
  12. 2018 Medium

    Identified redox control of SMYD2 by showing Cys13 glutathionylation disrupts the protective HSP90-titin complex, linking oxidative stress to sarcomere destabilization.

    Evidence Clickable glutathione labeling, Co-IP, and MMP-2/calpain proteolysis assays

    PMID:30337525

    Open questions at the time
    • In vivo demonstration of Cys13 glutathionylation in disease lacking
    • Reversibility/enzymatic deglutathionylation not addressed
  13. 2019 Medium

    Refined the SMYD2 recognition motif and linked methylation to protein-stability control of oncogenic substrates.

    Evidence Peptide-array specificity profiling with substrate validation, and EZH2 K307 methylation/stability assays with LSD1 reversal

    PMID:31612581 PMID:31693890

    Open questions at the time
    • Motif does not predict in-cell methylation reliably
    • Generality of methylation-stabilization mechanism unclear
  14. 2020 Medium

    Placed SMYD2 in a CDK4/6 feedback circuit and extended its activity to tubulin and ciliogenesis, coupling cell-cycle signaling to cytoskeletal dynamics.

    Evidence Kinase and methyltransferase assays, CDK4/6 inhibition, SMYD2 depletion, and cilia assembly assays

    PMID:33127671

    Open questions at the time
    • CDK4/6 phosphosite on SMYD2 not mapped
    • α-tubulin methylation site and stoichiometry undefined
  15. 2022 Medium

    Established SMYD2 as a regulator of DNA repair, cell-death, and protein turnover with immune and therapeutic consequences.

    Evidence Ku70 site-specific methylation with NHEJ/cGAS-STING readouts, RIPK1 methylation/death-signaling assays, c-Myc methylation/ubiquitination/GLS1 assays, and STUB1-mediated SMYD2 degradation Co-IP/knockdown

    PMID:35022391 PMID:35939202 PMID:36611819 PMID:37315132

    Open questions at the time
    • RIPK1 and SMAD-related methylation sites not all mapped
    • STUB1 ubiquitination of SMYD2 not reconstituted (Low confidence)
  16. 2024 Medium

    Defined SMYD2 as a driver of metastasis and therapy resistance through reader-mediated migration and stabilization of hormone receptors, with mechanism-specific in vivo genetic validation.

    Evidence BCAR3 K334me1/FMNL reader and mammary-specific KO metastasis assays, KMT2D K1330 methylation/ChIP/PI3K-inhibitor sensitization, PPARγ methylation/nuclear translocation in pulmonary hypertension, and AR methylation/stability in CRPC

    PMID:38243079 PMID:38296970 PMID:38700982 PMID:38770649

    Open questions at the time
    • Tissue-specific selectivity among these substrates unresolved
    • Several mechanisms validated in single labs

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how SMYD2 selects among its many substrates in a given cell type and how its catalytic versus scaffolding functions are partitioned across compartments.
  • No quantitative framework for in-cell substrate prioritization
  • Demethylases for many sites unidentified
  • Physiological versus oncogenic substrate hierarchy unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 8 GO:0140096 catalytic activity, acting on a protein 8 GO:0042393 histone binding 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-4839726 Chromatin organization 4 R-HSA-1640170 Cell Cycle 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-73894 DNA Repair 2
Partners
BCAR3ESR1EZH2HSP90AB1L3MBTL1RB1STUB1TP53
Complex memberships
Sin3A histone deacetylase complexSmyd2-HSP90-titin N2A complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 SMYD2 methylates p53 at lysine 370 (monomethylation), repressing p53-mediated transcriptional activity. Set9-mediated methylation of p53 K372 inhibits SMYD2-mediated K370 methylation in part by blocking the p53-SMYD2 interaction, establishing cross-talk between activating and repressing lysine methylation marks on p53. In vitro methyltransferase assay, siRNA knockdown, co-immunoprecipitation, apoptosis assays Nature High 17108971
2006 SMYD2 mediates histone H3K36 dimethylation via its SET domain, represses transcription from a reporter, and associates specifically with the Sin3A histone deacetylase complex. Overexpressed SMYD2 localizes to both cytoplasm and nucleus. Histone methyltransferase assay, co-immunoprecipitation with Sin3A complex, reporter gene assay, subcellular localization by immunofluorescence Molecular cancer Medium 16805913
2007 SMYD2 interacts with HSP90α independently of its SET and MYND domains, and this interaction enhances SMYD2 histone methyltransferase activity and specificity for H3K4 in vitro. SMYD2 interacts with EBP41L3 through the MYND domain and with p53 through the SET domain. Immunoprecipitation coupled to mass spectrometry, co-immunoprecipitation, in vitro methyltransferase assay, chromatin IP Molecular & cellular proteomics : MCP Medium 18065756
2010 SMYD2 methylates RB at lysine 860 in vitro and in cells; this monomethylation provides a direct binding site for the methyl-binding domain of the transcriptional repressor L3MBTL1. Methylation is regulated during cell cycle progression, differentiation, and in response to DNA damage. In vitro methyltransferase assay, mass spectrometry, pulldown with L3MBTL1 methyl-binding domain, cell-cycle analysis The Journal of biological chemistry High 20870719
2011 Crystal structures of SMYD2 in complex with p53 substrate and product peptides, and with the inhibitor AZ505, reveal that the substrate (p53 peptide) binds in the peptide-binding groove between the SET domain and C-terminal domain (CTD), and that AZ505 is a substrate-competitive inhibitor occupying this same groove. X-ray crystallography, high-throughput chemical screen, biochemical inhibition assays Structure High 21782458
2011 Crystal structures of SMYD2 bound to cofactor product S-adenosylhomocysteine or inhibitor sinefungin reveal that the CTD stabilizes an autoinhibited conformation and restricts access to the catalytic site; sinefungin binding causes outward bending of the first two CTD helices, demonstrating conformational flexibility of the TPR-like CTD. X-ray crystallography PloS one High 21738746
2011 Crystal structure of full-length SMYD2 in complex with SAM cofactor and p53 peptide shows the substrate binds in a U-shaped conformation in a deep pocket between the SET domain and CTD. The tetratricopeptide repeat (TPR) motif of the CTD and an EDEE motif are critical for p53 substrate binding specificity; deletion of CTD or mutation of EDEE impairs SMYD2 methylation of p53. X-ray crystallography, domain deletion and site-directed mutagenesis, in vitro methyltransferase assay The Journal of biological chemistry High 21880715
2011 SMYD2 methylates HSP90 at K209 and K615 (nucleotide-binding and dimerization domains, respectively); each methylation site shows unique reactivity to HSP90 co-chaperones, pH, and demethylation by LSD1. Proteomic interactome mapping, Co-IP, in vitro methyltransferase assay, mass spectrometry Journal of molecular cell biology Medium 22028380
2012 SMYD2 methylates the cytoplasmic chaperone HSP90 in multiple cell types; in muscle, HSP90 methylation promotes formation of a Smyd2–Hsp90–titin (N2A domain) complex. Smyd2 deficiency causes loss of Hsp90 methylation, impaired titin stability, and altered skeletal muscle function. In vitro methyltransferase assay, co-immunoprecipitation, zebrafish morpholino knockdown, muscle function assays Genes & development High 22241783
2012 SMYD2 methylates RB1 at lysine 810 (identified by LC-MS/MS); this methylation enhances Ser807/811 phosphorylation of RB1 both in vitro and in vivo, accelerates E2F transcriptional activity, and promotes G1/S cell cycle progression. In vitro methyltransferase assay, LC-MS/MS, in vivo methylation/phosphorylation assays, E2F reporter, cell cycle analysis, siRNA knockdown Neoplasia High 22787429
2012 Smyd2 associates with the sarcomeric I-band at the titin N2A domain in cardiomyocytes; binding to N2A occurs in vitro and in yeast via N-terminal and extreme C-terminal regions of Smyd2. Smyd2 knockdown in zebrafish strongly impairs cardiac performance. In vitro binding assay, yeast two-hybrid, zebrafish morpholino knockdown, cardiac function measurement Biochimica et biophysica acta Medium 23047121
2013 SMYD2 directly methylates ERα at lysine 266 (K266) in vitro and in MCF7 cells; this methylation attenuates chromatin recruitment of ERα and represses ERα target gene activation under estrogen-depleted conditions. Upon estrogen stimulation, K266 methylation is diminished, enabling p300/CBP to acetylate K266 and promote ERα transactivation, establishing cross-talk between SMYD2-mediated methylation and acetylation. In vitro methyltransferase assay, chromatin immunoprecipitation, gene expression analysis, siRNA knockdown PNAS High 24101509
2014 Crystal structure of SMYD2 in complex with an ERα K266-containing peptide shows ERα binds in a U-shaped conformation with binding specificity determined mainly by residues C-terminal to the target lysine. Comparison with SMYD2–p53 structure reveals distinct substrate binding modes underlying SMYD2's broad substrate specificity. X-ray crystallography Journal of molecular biology High 24594358
2014 SMYD2 monomethylates PARP1 at lysine 528 (confirmed by LC-MS/MS and Edman degradation); methylated PARP1 shows enhanced poly(ADP-ribose) formation after oxidative stress, positively regulating PARP1 poly(ADP-ribosyl)ation activity. In vitro methyltransferase assay, LC-MS/MS, Edman degradation, PAR formation assay Neoplasia High 24726141
2014 SMYD2 methylates HSP90AB1 at lysines 531 and 574; these methylation sites are important for HSP90AB1 dimerization and chaperone complex formation. HSP90AB1 interacts with SMYD2 through the C-terminal region of HSP90AB1 and the SET domain of SMYD2. In vitro and in vivo methyltransferase assays, mass spectrometry, co-immunoprecipitation, proliferation assays Cancer letters Medium 24880080
2015 SMYD2 methylates PTEN at lysine 313 in vitro and in vivo; K313 methylation negatively regulates PTEN tumor suppressor activity, attenuates PTEN S380 phosphorylation, and results in AKT pathway activation. SMYD2 knockdown reduces AKT phosphorylation in breast cancer cells. In vitro methyltransferase assay, MS confirmation, site-directed mutagenesis (K313A), phosphorylation assays, siRNA knockdown Neoplasia High 25925379
2015 SMYD2 is primarily cytoplasmic by subcellular fractionation; inhibition with LLY-507 does not significantly affect global histone methylation levels (by MS-based proteomics), suggesting SMYD2 targets non-histone substrates or a small subset of histones at specific loci. Subcellular fractionation, SILAC-based mass spectrometry, selective inhibitor treatment The Journal of biological chemistry Medium 25825497
2015 Smyd2 specifically facilitates H3K36 dimethylation at TNF and IL6 gene promoters in macrophages, suppressing their transcription and inhibiting NF-κB and ERK signaling, resulting in reduced macrophage activation and M1 polarization. ChIP assay, siRNA knockdown, cytokine measurement, signaling pathway analysis The Journal of biological chemistry Medium 25583990
2016 SILAC-based proteomics identified 35 cellular monomethyl-lysine (Kme1) sites potently down-regulated by both shRNA knockdown and the selective SMYD2 inhibitor LLY-507 in ESCC cells, including BTF3-K2, PDAP1-K126, and numerous sites in AHNAK and AHNAK2, revealing diverse SMYD2 substrate specificity in cells. SILAC, immunoaffinity enrichment of Kme1 peptides, mass spectrometry, shRNA knockdown, small molecule inhibitor Molecular & cellular proteomics : MCP High 26750096
2016 SMYD2 was identified as essential for robust BMP- (but not TGFβ-) induced target gene expression; SMYD2 methylates the kinase domain of BMPR2 (BMP type II receptor), promoting BMPR2 kinase activity and downstream SMAD1/5 phosphorylation and nuclear localization. RNAi screen, CRISPR/Cas9 knockout, shRNA knockdown, in vitro methyltransferase assay, SMAD1/5 phosphorylation assays, nuclear localization assay The Journal of biological chemistry Medium 28588028
2017 SMYD2 associates with latent HIV-1 promoter chromatin enriched in H4K20me1; SMYD2 knockdown or pharmacological inhibition reactivates latent HIV-1 in T cells. L3MBTL1, a chromatin-compacting H4K20me1 reader, is recruited to the latent HIV-1 promoter in a SMYD2-dependent manner. RNAi screen, pharmacological inhibition, chromatin immunoprecipitation, HIV latency reactivation assay Cell host & microbe Medium 28494238
2017 SMYD2 methylates β-catenin at lysine 133; K133 methylation is critical for β-catenin nuclear translocation and interaction with FOXM1. K133A substitution almost completely abolishes nuclear localization. SMYD2 knockdown reduces nuclear β-catenin and downstream Wnt target gene expression. In vitro methyltransferase assay, site-directed mutagenesis (K133A), nuclear fractionation, co-immunoprecipitation, gene expression analysis Oncotarget Medium 28915556
2017 SMYD2 methylates ALK at lysines 1451, 1455, and 1610; K1610A substitution reduces AKT phosphorylation and cell growth, and SMYD2 knockdown attenuates EML4-ALK phosphorylation in NSCLC cells. In vitro methyltransferase assay, site-directed mutagenesis, phosphorylation assays, siRNA knockdown, cell proliferation assay Cancer science Medium 28370702
2017 SMYD2 carries out its pro-cystic function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased renal epithelial cell proliferation and survival. Two positive feedback loops were identified: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. In vivo Pkd1 knockout mouse models, pharmacological inhibition with AZ505, in vitro methyltransferase assay, signaling pathway analysis The Journal of clinical investigation Medium 28604386
2018 SMYD2 glutathionylation at Cys13 (identified by clickable glutathione approach) causes loss of its interaction with Hsp90 and the titin N2A domain. Upon dissociation, titin/N2A is degraded by activated MMP-2, establishing a mechanism by which ROS-induced SMYD2 glutathionylation leads to sarcomere destabilization. Clickable glutathione labeling, biochemical Co-IP, proteolysis assays with MMP-2 and calpain 1 Nature communications Medium 30337525
2018 HSP90 and co-chaperone P23 contain a (M/I/L/V)PXL motif at their C-termini that mediates interaction with SMYD2 independently of the HSP90 EEVD motif. In a reconstituted bacterial system, SMYD2 binding to HSP90/P23 considerably increases methylation of ERα K266, linking chaperone complex formation to ERα methylation efficiency. Alpha proximity assay, synthetic peptide competition, bacterial reconstitution system, in vitro methyltransferase assay The Journal of biological chemistry Medium 30190324
2019 SMYD2 directly methylates EZH2 at lysine 307 (K307), enhancing EZH2 protein stability; LSD1 can reverse this methylation. SMYD2-mediated EZH2 K307 methylation promotes breast cancer cell proliferation, EMT, and invasion through stabilized EZH2 function. In vitro methyltransferase assay, mass spectrometry, co-immunoprecipitation, protein stability assay, siRNA knockdown Cell reports Medium 31693890
2019 Peptide array profiling of SMYD2 substrate specificity revealed preference for leucine (or phenylalanine) at the -1 position and disfavor of acidic residues at +1 to +3 positions; using this motif, 32 novel peptide substrates and 14 novel protein substrates were identified by in vitro methyltransferase assays. Peptide arrays, in vitro methyltransferase assays Chembiochem Medium 31612581
2019 Six novel SMYD2 substrates (MAPT, CCAR2, EEF2, NCOA3, STUB1, UTP14A) were confirmed by immunoprecipitation in cells; methylation was abrogated by the selective SMYD2 inhibitor BAY-598, confirming dependence on SMYD2 catalytic activity. Bioinformatic prediction, co-immunoprecipitation, selective inhibitor treatment Journal of proteome research Medium 27163177
2020 CDK4/6 directly phosphorylates SMYD2, positively regulating its enzymatic activity; SMYD2 in turn positively regulates CDK4/6 expression. SMYD2 functions as an α-tubulin methyltransferase, connecting CDK4/6-SMYD2 signaling to microtubule dynamics and ciliogenesis. Kinase assay, in vitro methyltransferase assay, CDK4/6 inhibitor treatment, SMYD2 depletion, cilia assembly assay Science advances Medium 33127671
2021 SMYD2 methylates TRAF2 in the cytoplasm; SMYD2-mediated TRAF2 methylation stabilizes TRAF2 against proteolysis and enhances NF-κB signaling activity. LSD1 demethylates TRAF2 to counteract this modification. Mass spectrometry, pulldown, co-immunoprecipitation, methyltransferase assay, ubiquitination assay, luciferase reporter, in vivo inflammation models Clinical and translational medicine Medium 34841684
2022 SMYD2 methylates Ku70 at lysines 74, 516, and 539 in response to DNA damage, leading to increased recruitment of the Ku70/Ku80/DNA-PKcs complex to DNA damage sites and promoting NHEJ repair. SMYD2 inhibition causes persistent DNA damage, cytosolic DNA accumulation, and activation of the cGAS-STING pathway with increased CD8+ T cell infiltration. Co-IP, in vitro methyltransferase assay (Ku70), DNA damage response assays, cGAS-STING pathway analysis, immune cell profiling Science advances Medium 37315132
2022 SMYD2 methylates RIPK1 and inhibits RIPK1 phosphorylation, thereby restricting TNF-induced apoptosis and necroptosis in colon tumor cells and supporting tumor growth. SMYD2 deficiency experiments, RIPK1 phosphorylation assays, apoptosis/necroptosis assays, tumor growth models Cell death & disease Medium 35022391
2022 STUB1 (an E3 ubiquitin ligase) mediates ubiquitin-dependent degradation of SMYD2 in response to cisplatin treatment; STUB1 knockdown reverses SMYD2 degradation and impairs cisplatin efficacy in glioma cells. UbiBrowser prediction, co-IP, siRNA knockdown, protein stability assay Journal of molecular neuroscience Low 35939202
2022 SMYD2 methylates c-Myc to increase its protein stability by reducing K48-linked polyubiquitination and proteasomal degradation; stabilized c-Myc upregulates GLS1, promoting glutamine metabolism in hepatocellular carcinoma. Co-IP, ubiquitination assay, in vitro methyltransferase assay, siRNA knockdown, gene expression analysis Cells Medium 36611819
2022 SMYD2 regulates VSMC contractile phenotype by promoting expression and transactivation of myocardin; myocardin directly interacts with SMYD2 and facilitates SMYD2 recruitment to CArG regions of SMC contractile gene promoters, where SMYD2-mediated H3K4 methylation creates an open chromatin state. SMYD2 ablation in VSMCs exacerbates neointima formation. SMC-specific SMYD2 knockout mice, genome-wide transcriptome analysis, ChIP, Co-IP, carotid artery injury model Cellular and molecular life sciences Medium 37615725
2023 SMYD2 directly methylates SMAD3, and epigenetic regulation by SMYD2 upregulates SMAD3 expression, thereby promoting lung cancer metastasis. SMYD2 knockdown reduces SMAD3 levels and cell migration/invasion. siRNA knockdown, in vitro EMT system, ChIP, in vivo metastasis models Experimental & molecular medicine Low 37121971
2023 SMYD2 promotes HDAC3 expression via H3K36 trimethylation at the HDAC3 promoter; HDAC3 then directly interacts with and deacetylates SRF, enhancing SRF transcriptional activity and VSMC proliferation. SMYD2 knockdown represses SRF target genes and inhibits neointima formation. Transcriptome sequencing, ChIP, Co-IP, Smyd2-vTg mouse, carotid injury model, HDAC3 inhibitor studies Acta pharmaceutica sinica. B Medium 38322347
2024 SMYD2 methylates KMT2D at K1330, adjacent to the PI3K-regulated S1331 phosphorylation site; K1330 methylation promotes KMT2D chromatin binding. SMYD2 loss attenuates alpelisib-induced KMT2D binding and ERα-dependent transcription, and sensitizes ER+ breast cancer cells to PI3K/AKT inhibition. In vitro methyltransferase assay, ChIP, gene expression analysis, siRNA knockdown, pharmacological inhibition, patient-derived organoids Cell reports Medium 38700982
2024 SMYD2 monomethylates BCAR3 at lysine 334 (K334me1) in breast cancer cells; K334me1 is recognized by a novel methyl-binding domain in FMNL proteins, recruiting them to cell edges to modulate lamellipodia properties and promote cancer cell migration and invasion. Mammary-epithelium-specific SMYD2 ablation blocks metastasis without affecting primary tumor growth. In vitro methyltransferase assay, site-directed mutagenesis, methyl-binding domain pulldown, live imaging, SMYD2 mammary-specific KO mouse, in vivo metastasis assay Cell discovery High 38296970
2024 SMYD2 methylates PPARγ, inhibiting its nuclear translocation and transcriptional activity; suppression of PPARγ by SMYD2-mediated methylation promotes mitophagy and PASMC hyperproliferation, contributing to pulmonary hypertension. PPARγ agonist rosiglitazone largely abolishes the detrimental effects of SMYD2 overexpression. In vitro interaction and methyltransferase assays, SMYD2-vTg mice, LLY-507 pharmacological inhibition, nuclear fractionation, mitophagy assays, hypoxia-induced PH model Circulation research Medium 38770649
2024 SMYD2 methylates androgen receptor (AR), promoting AR stability by reducing ubiquitination and proteasomal degradation, thereby enhancing AR transcriptome activity and CRPC resistance to enzalutamide. Co-IP, in vitro methyltransferase assay, ubiquitination assay, AR transcriptome analysis, siRNA knockdown, AZ505 pharmacological inhibition, mouse xenograft Oncogene Medium 38243079

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Repression of p53 activity by Smyd2-mediated methylation. Nature 521 17108971
2006 Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Molecular cancer 252 16805913
2010 Methylation of the retinoblastoma tumor suppressor by SMYD2. The Journal of biological chemistry 181 20870719
2012 RB1 methylation by SMYD2 enhances cell cycle progression through an increase of RB1 phosphorylation. Neoplasia (New York, N.Y.) 169 22787429
2011 Structural basis of substrate methylation and inhibition of SMYD2. Structure (London, England : 1993) 168 21782458
2007 The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Molecular & cellular proteomics : MCP 167 18065756
2009 Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 148 19423649
2012 Smyd2 controls cytoplasmic lysine methylation of Hsp90 and myofilament organization. Genes & development 138 22241783
2013 Regulation of estrogen receptor α by histone methyltransferase SMYD2-mediated protein methylation. Proceedings of the National Academy of Sciences of the United States of America 126 24101509
2017 Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease. The Journal of clinical investigation 108 28604386
2015 LLY-507, a Cell-active, Potent, and Selective Inhibitor of Protein-lysine Methyltransferase SMYD2. The Journal of biological chemistry 99 25825497
2014 The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. Neoplasia (New York, N.Y.) 94 24726141
2015 The histone methyltransferase Smyd2 is a negative regulator of macrophage activation by suppressing interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) production. The Journal of biological chemistry 92 25583990
2011 Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2. Journal of molecular cell biology 91 22028380
2016 Quantitative Profiling of the Activity of Protein Lysine Methyltransferase SMYD2 Using SILAC-Based Proteomics. Molecular & cellular proteomics : MCP 90 26750096
2018 Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. Cell death & disease 86 29487338
2017 SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency. Cell host & microbe 86 28494238
2014 Overexpression of SMYD2 contributes to malignant outcome in gastric cancer. British journal of cancer 84 25321194
2014 SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. Cancer letters 82 24880080
2015 Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN. Neoplasia (New York, N.Y.) 81 25925379
2019 Histone methyltransferase SMYD2: ubiquitous regulator of disease. Clinical epigenetics 78 31370883
2012 Lysine methyltransferase Smyd2 regulates Hsp90-mediated protection of the sarcomeric titin springs and cardiac function. Biochimica et biophysica acta 73 23047121
2016 Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes & development 72 26988419
2019 Regulation of EZH2 by SMYD2-Mediated Lysine Methylation Is Implicated in Tumorigenesis. Cell reports 71 31693890
2016 Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. Journal of medicinal chemistry 70 27075367
2010 Cardiac deletion of Smyd2 is dispensable for mouse heart development. PloS one 63 20305823
2019 Inhibition of SMYD2 suppresses tumor progression by down-regulating microRNA-125b and attenuates multi-drug resistance in renal cell carcinoma. Theranostics 58 31754403
2011 Structure of human SMYD2 protein reveals the basis of p53 tumor suppressor methylation. The Journal of biological chemistry 57 21880715
2015 Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2. ACS medicinal chemistry letters 52 26101576
2018 Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation. PloS one 51 29856759
2014 Structural insights into estrogen receptor α methylation by histone methyltransferase SMYD2, a cellular event implicated in estrogen signaling regulation. Journal of molecular biology 49 24594358
2018 SMYD2 promoter DNA methylation is associated with abdominal aortic aneurysm (AAA) and SMYD2 expression in vascular smooth muscle cells. Clinical epigenetics 44 29507647
2021 SMYD2 promotes tumorigenesis and metastasis of lung adenocarcinoma through RPS7. Cell death & disease 40 33935284
2020 Cross-talk between CDK4/6 and SMYD2 regulates gene transcription, tubulin methylation, and ciliogenesis. Science advances 40 33127671
2017 Critical roles of SMYD2-mediated β-catenin methylation for nuclear translocation and activation of Wnt signaling. Oncotarget 40 28915556
2024 SMYD2-Methylated PPARγ Facilitates Hypoxia-Induced Pulmonary Hypertension by Activating Mitophagy. Circulation research 39 38770649
2014 Lysine methyltransferase Smyd2 suppresses p53-dependent cardiomyocyte apoptosis. Biochimica et biophysica acta 39 25014164
2017 Effects of SMYD2-mediated EML4-ALK methylation on the signaling pathway and growth in non-small-cell lung cancer cells. Cancer science 36 28370702
2011 Crystal structures of histone and p53 methyltransferase SmyD2 reveal a conformational flexibility of the autoinhibitory C-terminal domain. PloS one 36 21738746
2019 Small-molecule inhibitors of lysine methyltransferases SMYD2 and SMYD3: current trends. Future medicinal chemistry 33 30998113
2019 Inhibition of SMYD2 Sensitized Cisplatin to Resistant Cells in NSCLC Through Activating p53 Pathway. Frontiers in oncology 31 31106145
2018 SMYD2 glutathionylation contributes to degradation of sarcomeric proteins. Nature communications 31 30337525
2021 SMYD2-mediated TRAF2 methylation promotes the NF-κB signaling pathways in inflammatory diseases. Clinical and translational medicine 30 34841684
2020 SMYD2 suppresses APC2 expression to activate the Wnt/β-catenin pathway and promotes epithelial-mesenchymal transition in colorectal cancer. American journal of cancer research 30 32266106
2016 Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors. Journal of medicinal chemistry 30 28002961
2015 The selective activation of p53 target genes regulated by SMYD2 in BIX-01294 induced autophagy-related cell death. PloS one 30 25562686
2022 SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth. Cell death & disease 29 35022391
2023 SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity. Science advances 28 37315132
2023 Epigenetic regulation of SMAD3 by histone methyltransferase SMYD2 promotes lung cancer metastasis. Experimental & molecular medicine 27 37121971
2021 LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer. Cancer cell international 27 34544413
2019 Histone methyltransferase SMYD2 selective inhibitor LLY-507 in combination with poly ADP ribose polymerase inhibitor has therapeutic potential against high-grade serous ovarian carcinomas. Biochemical and biophysical research communications 27 30955858
2022 SMYD2 Promotes Hepatocellular Carcinoma Progression by Reprogramming Glutamine Metabolism via c-Myc/GLS1 Axis. Cells 26 36611819
2019 SMYD2 promotes cervical cancer growth by stimulating cell proliferation. Cell & bioscience 26 31548876
2017 The lysine methyltransferase SMYD2 methylates the kinase domain of type II receptor BMPR2 and stimulates bone morphogenetic protein signaling. The Journal of biological chemistry 26 28588028
2015 SMYD2 overexpression is associated with tumor cell proliferation and a worse outcome in human papillomavirus-unrelated nonmultiple head and neck carcinomas. Human pathology 26 26826421
2013 SMYD2 is induced during cell differentiation and participates in early development. The International journal of developmental biology 26 23873367
2016 Residual expression of SMYD2 and SMYD3 is associated with the acquisition of complex karyotype in chronic lymphocytic leukemia. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 25 26790435
2021 Critical roles of SMYD2 lysine methyltransferase in mediating renal fibroblast activation and kidney fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 34143514
2019 SMYD2-OE promotes oxaliplatin resistance in colon cancer through MDR1/P-glycoprotein via MEK/ERK/AP1 pathway. OncoTargets and therapy 24 31040701
2016 An Integrative Proteomic Approach Identifies Novel Cellular SMYD2 Substrates. Journal of proteome research 24 27163177
2023 Neutrophil extracellular traps promote gastric cancer cell metastasis via the NAT10-mediated N4-acetylcytidine modification of SMYD2. Cellular signalling 22 38110168
2022 Histone methyltransferase Smyd2 contributes to blood-brain barrier breakdown in stroke. Clinical and translational medicine 22 35297562
2022 Oleocanthal Attenuates Metastatic Castration-Resistant Prostate Cancer Progression and Recurrence by Targeting SMYD2. Cancers 21 35884603
2022 Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer. Angiogenesis 20 35503397
2021 SMYD2 suppresses p53 activity to promote glucose metabolism in cervical cancer. Experimental cell research 20 34015314
2008 smyd1 and smyd2 are expressed in muscle tissue in Xenopus laevis. Cytotechnology 20 19003161
2024 Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis. Cell discovery 19 38296970
2022 Cross talk between lysine methyltransferase Smyd2 and TGF-β-Smad3 signaling promotes renal fibrosis in autosomal dominant polycystic kidney disease. American journal of physiology. Renal physiology 19 35759739
2020 The histone methyltransferase SMYD2 is a novel therapeutic target for the induction of apoptosis in ovarian clear cell carcinoma cells. Oncology letters 19 32934721
2019 SMYD2 Drives Mesendodermal Differentiation of Human Embryonic Stem Cells Through Mediating the Transcriptional Activation of Key Mesendodermal Genes. Stem cells (Dayton, Ohio) 19 31348575
2019 Analysis of the Substrate Specificity of the SMYD2 Protein Lysine Methyltransferase and Discovery of Novel Non-Histone Substrates. Chembiochem : a European journal of chemical biology 19 31612581
2022 Ranunculus ternatus Thunb extract attenuates renal fibrosis of diabetic nephropathy via inhibiting SMYD2. Pharmaceutical biology 18 35142600
2018 A motif in HSP90 and P23 that links molecular chaperones to efficient estrogen receptor α methylation by the lysine methyltransferase SMYD2. The Journal of biological chemistry 18 30190324
2016 Smyd2 is a Myc-regulated gene critical for MLL-AF9 induced leukemogenesis. Oncotarget 18 27655694
2023 The lysine methyltransferase SMYD2 facilitates neointimal hyperplasia by regulating the HDAC3-SRF axis. Acta pharmaceutica Sinica. B 17 38322347
2017 SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress. Oncotarget 17 28187429
2022 Protein Lysine Methyltransferase SMYD2: A Promising Small Molecule Target for Cancer Therapy. Journal of medicinal chemistry 16 35914250
2020 LncRNA NEAT1 promotes cardiac hypertrophy through microRNA-19a-3p/SMYD2 axis. European review for medical and pharmacological sciences 16 32096186
2022 The lysine methyltransferases SET and MYND domain containing 2 (Smyd2) and Enhancer of Zeste 2 (Ezh2) co-regulate osteoblast proliferation and mineralization. Gene 15 36191822
2020 SMYD2 facilitates cancer cell malignancy and xenograft tumor development through ERBB2-mediated FUT4 expression in colon cancer. Molecular and cellular biochemistry 15 32342276
2024 Lysine methyltransferase SMYD2 enhances androgen receptor signaling to modulate CRPC cell resistance to enzalutamide. Oncogene 14 38243079
2023 Long noncoding RNA DLEU1 promotes proliferation and glycolysis of gastric cancer cells via APOC1 upregulation by recruiting SMYD2 to induce trimethylation of H3K4 modification. Translational oncology 14 37478669
2022 Pharmacological inhibition of SMYD2 protects against cisplatin-induced acute kidney injury in mice. Frontiers in pharmacology 14 36046818
2021 Novel insights into SMYD2 and SMYD3 inhibitors: from potential anti-tumoural therapy to a variety of new applications. Molecular biology reports 13 34510321
2023 Targeting SMYD2 inhibits prostate cancer cell growth by regulating c-Myc signaling. Molecular carcinogenesis 12 37036190
2022 Baicalein Inhibits the SMYD2/RPS7 Signaling Pathway to Inhibit the Occurrence and Metastasis of Lung Cancer. Journal of oncology 12 35432530
2022 STUB1-SMYD2 Axis Regulates Drug Resistance in Glioma cells. Journal of molecular neuroscience : MN 12 35939202
2024 Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer. Cell reports 11 38700982
2022 SMYD2 aggravates gastrointestinal stromal tumor via upregulation of EZH2 and downregulation of TET1. Cell death discovery 11 35668081
2016 Conformational Dynamics of Lysine Methyltransferase Smyd2. Insights into the Different Substrate Crevice Characteristics of Smyd2 and Smyd3. Journal of chemical information and modeling 11 27959541
2015 Molecular Dynamics Simulation Reveals Correlated Inter-Lobe Motion in Protein Lysine Methyltransferase SMYD2. PloS one 11 26717235
2023 SMYD2 regulates vascular smooth muscle cell phenotypic switching and intimal hyperplasia via interaction with myocardin. Cellular and molecular life sciences : CMLS 10 37615725
2025 The Olive Oil Phenolic S-(-)-Oleocanthal Suppresses Colorectal Cancer Progression and Recurrence by Modulating SMYD2-EZH2 and c-MET Activation. Nutrients 9 39940255
2023 Pharmacological inhibition of SMYD2 protects against cisplatin-induced renal fibrosis and inflammation. Journal of pharmacological sciences 9 37524453
2022 Histone methyltransferase Smyd2 drives adipogenesis via regulating STAT3 phosphorylation. Cell death & disease 9 36270984
2008 Tumor slices as a model to evaluate doxorubicin in vitro treatment and expression of trios of genes PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2 in canine mammary gland cancer. Acta veterinaria Scandinavica 9 18601734
2020 The lysine methyltransferase SMYD2 is required for normal lymphocyte development and survival of hematopoietic leukemias. Genes and immunity 8 32115575
2020 Synthesis and structure-activity relationship studies of LLY-507 analogues as SMYD2 inhibitors. Bioorganic & medicinal chemistry letters 8 33011288
2022 SMYD2 Inhibition Downregulates TMPRSS2 and Decreases SARS-CoV-2 Infection in Human Intestinal and Airway Epithelial Cells. Cells 7 35455942
2022 SMYD2 epigenetically activates MEX3A and suppresses CDX2 in colorectal cancer cells to augment cancer growth. Clinical and experimental pharmacology & physiology 7 35637161

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