SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells

Vougiouklakis, Theodore; Sone, Kenbun; Saloura, Vassiliki; Cho, Hyun Soo; Suzuki, Takehiro; Dohmae, Naoshi; Alachkar, Houda; Nakamura, Yusuke; Hamamoto, Ryuji

doi:10.18632/oncotarget.6351

Cited by 29 publications

(42 citation statements)

References 50 publications

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“…1c). Quantitative analysis of these results revealed that SUV4-20H1 exhibits 10 fold more activity on monomethylated (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) arrays containing unmethylated (me0) and mono-methylated (me1) lysine 20 and a mutant peptide (K20 A) by SUV4-20H1 and SUV4-20H2 (incubation times 60 min in each case). The autoradiography image indicates the transfer of the radioactively labeled methyl groups to the peptides.…”

Section: Resultsmentioning

confidence: 98%

“…We, therefore, aimed to test the activity of these proteins on H4 peptide substrates with different methylation states of K20. 15 amino acid long peptides with the sequence of the H4 tail (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) containing K20 at the center were synthesized on cellulose membrane using the SPOT synthesis method [28]. SPOT-arrays containing different forms of H4K20 (H4K20me1, H4K20me0 and H4K20A) peptides were methylated with SUV4-20H proteins using radioactively labeled [methyl-3 H]-AdoMet as a cofactor.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the sequence recognition motif of SUV4-20H2 is more narrow than SUV4-20H1 (readout of SUV4-20H2 is observed only between R19 and D24) and in general it shows less specificity. Unlike (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) peptide array methylated by SUV4-20H1. The peptide array was synthesized using the H4 (13-27) sequence as a template.…”

Section: Substrate Sequence Specificity Of Suv4-20h Proteinsmentioning

confidence: 99%

“…The extracellular signal-regulated kinase 1 (ERK1) was reported to be trimethylated by SUV4-20H1 at two different sites: K302 and K361. ERK1 has an important role in cancer [26], its methylation was reported to increase its phosphorylation and transcription, which enhances the ERK1 signaling cascade and may lead to tumorigenesis [27].…”

Section: Introductionmentioning

confidence: 99%

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Specificity of the SUV4–20H1 and SUV4–20H2 protein lysine methyltransferases and methylation of novel substrates

Weirich

Kudithipudi

Jeltsch

2016

Journal of Molecular Biology

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Substrate Sequence Specificity Of Suv4-20h Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Specificity of the SUV4–20H1 and SUV4–20H2 protein lysine methyltransferases and methylation of novel substrates

Weirich

Kudithipudi

Jeltsch

2016

Journal of Molecular Biology

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“…Compared with the decades of studies of ERK1/2 phosphorylation, especially at the Thr202/Tyr204 sites in ERK1 and Thr185/Tyr187 in ERK2 of the Thr-X-Tyr motif, the studies of other PTMs of ERK1/2, including acetylation, methylation, and ubiquitination, are just emerging. Recently, two lysine sites at the ERK1 C-terminus, Lys302 and Lys361, have been revealed to be tri-methylated, and methylation of ERK1 enhances its phosphorylation (17). Arg309 of ERK1 has also been reported as a methylation site via a proteome-wide analysis, yet the function of this site is not clear (18).…”

mentioning

confidence: 99%

Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity

Xiang

Zhang

et al. 2018

Journal of Biological Chemistry

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Histone deacetylase 6 (HDAC6), a class IIb HDAC, plays an important role in many biological and pathological processes. Previously, we found that ERK1, a downstream kinase in the MAPK signaling pathway, phosphorylates HDAC6, thereby increasing HDAC6-mediated deacetylation of α-tubulin. However, whether HDAC6 reciprocally modulates ERK1 activity is unknown. Here, we report that both ERK1 and 2 are acetylated and that HDAC6 promotes ERK1 activity via deacetylation. Briefly, we found that both ERK1 and 2 physically interact with HDAC6. Endogenous ERK1/2 acetylation levels increased upon treatment with a pan-HDAC inhibitor, an HDAC6-specific inhibitor or depletion of HDAC6, suggesting that HDAC6 deacetylates ERK1/2. We also noted that the acetyltransferases CBP and p300 both can acetylate ERK1/2. Acetylated ERK1 exhibits reduced enzymatic activity toward the transcription factor ELK1, a well-known ERK1 substrate. Furthermore, mass spectrometry analysis indicated Lys-72 as an acetylation site in the ERK1 N-terminus, adjacent to Lys-71, which binds to ATP, suggesting that acetylation status of Lys-72 may affect ERK1 ATP binding. Interestingly, an acetylation-mimicking ERK1 mutant (K72Q) exhibited less phosphorylation than the WT enzyme and a deacetylationmimicking mutant (K72R). Of note, the K72Q mutant displayed decreased enzymatic activity in an in vitro kinase assay and in a cellular luciferase assay compared with the WT and K72R mutant. Taken together, our findings suggest that HDAC6 stimulates ERK1 activity. Along with our previous report that ERK1 promotes HDAC6 activity, we propose that HDAC6 and ERK1 may form a positive feedforward loop, which might play a role in cancer.Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are the enzymes that regulate core histones and non-histone proteins by deacetylation and acetylation, respectively (1). HATs acetylate proteins via adding acetyl groups to lysine residues, while HDACs catalyze a reverse reaction by removing the acetyl group from lysine residues. Up to now, a total of 18 HDACs are identified in humans and grouped HDAC6 deacetylates ERK12 into four classes based on their sequence similarity to yeast orthologs (2). Class I HDACs are homologous to yeast reduced potassium dependency 3 (Rpd3) and include HDACs 1, 2, 3 and 8. Class II HDACs are homologous to yeast histone deacetylase 1 (HdaI) and are further divided into class IIa and class IIb. Class IIa contains HDACs 4, 5, 7 and 9, and class IIb includes HDACs 6 and 10. HDAC11 is the only member in class IV. The deacetylase activity of HDAC classes I, II and IV is zinc-dependent. Class III HDACs, also knowns as sirtuins, are homologous to yeast silent information regulator 2 (Sir2), and the deacetylase activity of this class is oxidized nicotinamide adenine dinucleotide (NAD + )-dependent. HDAC6 belongs to class IIb HDACs. Its structure is quite unique among all HDACs, in that it contains two functional deacetylase domains in tandem and a zinc finger domain in the C-terminus (2,3). HDAC6...

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Differential effects by sex with Kmt5b loss

et al. 2021

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Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene‐trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. Lay Summary Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress‐induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD.

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SUV420H1 enhances the phosphorylation and transcription of ERK1 in cancer cells

Cited by 29 publications

References 50 publications

Specificity of the SUV4–20H1 and SUV4–20H2 protein lysine methyltransferases and methylation of novel substrates

Specificity of the SUV4–20H1 and SUV4–20H2 protein lysine methyltransferases and methylation of novel substrates

Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity

Differential effects by sex with Kmt5b loss

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