241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Nucleus Chromosome Note=Specificallylocalizes to mitotic chromosomes Colocalized with SIRT2 atmitotic foci Associates with chromosomes during mitosis;association is increased in a H(2)O(2)-induced oxidative stress-dependent manner Associates with silent chromatin on euchromaticarms Not associated with constitutive heterochromatin
Function (UniProt annotation)
Protein-lysine N-methyltransferase that monomethylatesboth histones and non-histone proteins Specificallymonomethylates 'Lys-20' of histone H4 (H4K20me1) H4K20me1 isenriched during mitosis and represents a specific tag forepigenetic transcriptional repression Mainly functions ineuchromatin regions, thereby playing a central role in thesilencing of euchromatic genes Required for cell proliferation,probably by contributing to the maintenance of proper higher-orderstructure of DNA during mitosis Involved in chromosomecondensation and proper cytokinesis Nucleosomes are preferred assubstrate compared to free histones Mediates monomethylation ofp53/TP53 at 'Lys-382', leading to repress p53/TP53-target genesPlays a negative role in TGF-beta response regulation and apositive role in cell migration
In mitotic prophase, the action of the condensin II complex enables initial chromosome condensation.The condensin II complex subunit NCAPD3 binds monomethylated histone H4 (H4K20me1), thereby associating with chromatin (Liu et al. 2010). Binding of the condensin II complex to chromatin is partially controlled by the presence of RB1 (Longworth et al. 2008). Two mechanisms contribute to the accumulation of H4K20me1 at mitotic entry. First, the activity of SETD8 histone methyltransferase peaks at G2/M transition (Nishioka et al. 2002, Rice et al. 2002, Wu et al. 2010). Second, the complex of CDK1 and cyclin B1 (CDK1:CCNB1) phosphorylates PHF8 histone demethylase at the start of mitosis, removing it from chromatin (Liu et al. 2010).Condensin II complex needs to be phosphorylated by the CDK1:CCNB1 complex, and then phosphorylated by PLK1, in order to efficiently condense prophase chromosomes (Abe et al. 2011)
Lysine methyltransferases (KMTs) and arginine methyltransferases (RMTs) have a common mechanism of catalysis. Both families transfer a methyl group from a common donor, S-adenosyl-L-methionine (SAM), to the nitrogen atom on the epsilon-amino group of lysine or arginine (Smith & Denu 2009) using a bimolecular nucleophillic substitution (SN2) methyl transfer mechanism (Smith & Denu 2009, Zhang & Bruice 2008). All human KMTs except DOT1L (KMT4) (Feng et al. 2002, van Leeuwen et al. 2002, Lacoste et al. 2002) have a ~130 amino acid catalytic domain referred to as the SET domain (Del Rizzo & Trievel 2011, Dillon et al. 2005, Herz et al. 2013). Some KMTs selectively methylate a particular lysine residue on a specific histone type. The extent of this methylation (mono-, di- or tri-methylation) also can be stringent (Herz et al. 2013, Copeland et al. 2009). Many KMTs also have non-histone substrates (Herz et al 2013), which are not discussed in this module.The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any processing. Histone literature typically refers to specific residues by numbers which are determined after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared to the histone literature.SET domain-containing proteins are classified in one of 7 families (Dillon et al. 2005). First to be discovered were the SUV39 family named after founding member SUV39H1 (KMT1A), which selectively methylates lysine-10 of histone H3 (H3K9) (Rea et al. 2000). Family member EHMT2 (KMT1C, G9A) is the predominant H3K9 methyltransferase in mammals (Tachibana et al. 2002). SETDB1 (KMT1E, ESET) also predominantly methylates H3K9, most effectively when complexed with ATF7IP (MCAF, hAM) (Wang et al. 2003). SETD2 (KMT3A, HYPB), a member of the SET2 family, specifically methylates histone H3 lysine-37 (H3K36) (Sun et al. 2005). WHSC1 (KMT3G, NSD2, MMSET) a member of the same family, targets H3K36 when provided with nucleosome substrates but also can methylate histone H4 lysine-45 when octameric native or recombinant nucleosome substrates are provided (Li et al. 2009); dimethylation of histone H3 at lysine-37 (H3K36me2) is thought to be the principal chromatin-regulatory activity of WHSC1 (Kuo et al. 2011). Relatives NSD1 (KMT3B) and WHSC1L1 (KMT3F, NSD3) also methylate nucleosomal H3K36. NSD1 is active on unmethylated or a mimetic monomethylated H3K36, but not di- or trimethylated H3K36 mimetics (Li et al. 2009). Human SETD7 (KMT7, SET7/9), not classified within the 7 SET-domain containing families, mono-methylates lysine-5 of histone H3 (H3K4) (Xiao et al. 2003)
TP53 (p53) undergoes methylation on several lysine and arginine residues, which modulates its transcriptional activity.
PRMT5, recruited to TP53 as part of the ATM-activated complex that includes TTC5, JMY and EP300 (p300), methylates TP53 arginine residues R333, R335 and R337. PRMT5-mediated methylation promotes TP53-stimulated expression of cell cycle arrest genes (Shikama et al. 1999, Demonacos et al. 2001, Demonacos et al. 2004, Adams et al. 2008, Adams et al. 2012). SETD9 (SET9) methylates TP53 at lysine residue K372, resulting in increased stability and activity of TP53 (Chuikov et al. 2004, Couture et al. 2006, Bai et al. 2011).
TP53 transcriptional activity is repressed by SMYD2-mediated methylation of TP53 at lysine residue K370 (Huang et al. 2006). Dimethylation of TP53 at lysine residue K373 by the complex of methyltransferases EHMT1 and EHMT2 also represses TP53-mediated transcription (Huang et al. 2010). The chromatin compaction factor L3MBTL1 binds TP53 monomethylated at lysine K382 by SETD8 (SET8) and, probably through changing local chromatin architecture, represses transcription of TP53 targets (West et al. 2010). The histone lysine-specific demethylase LSD1 interacts with TP53 and represses p53-mediated transcriptional activation (Huang et al. 2007). PRMT1 and CARM1 can also modulate p53 functions in a cooperative manner (An et al. 2004)
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