UniProt functional annotation for O14744



	UniProt functional annotation for O14744

UniProt code: O14744.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA (PubMed:10531356, PubMed:11152681, PubMed:11747828, PubMed:12411503, PubMed:15737618, PubMed:17709427, PubMed:20159986, PubMed:20810653, PubMed:21258366, PubMed:21917714, PubMed:22269951, PubMed:21081503). Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles (PubMed:12411503, PubMed:11747828, PubMed:17709427). Methylates SUPT5H and may regulate its transcriptional elongation properties (PubMed:12718890). Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development (By similarity). Methylates histone H3 'Arg-8', which may repress transcription (By similarity). Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage (By similarity). Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation (PubMed:21917714, PubMed:21258366). Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity (PubMed:21917714). Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9 (PubMed:22269951). Methylates and regulates SRGAP2 which is involved in cell migration and differentiation (PubMed:20810653). Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter (By similarity). Methylates GM130/GOLGA2, regulating Golgi ribbon formation (PubMed:20421892). Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner (PubMed:25284789). Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination (PubMed:26700805). Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression (PubMed:25092918). Symmetrically methylates NCL (PubMed:21081503). Methylates TP53; methylation might possibly affect TP53 target gene specificity (PubMed:19011621). Involved in spliceosome maturation and mRNA splicing in prophase I spermatocytes through the catalysis of the symmetrical arginine dimethylation of SNRPB (small nuclear ribonucleoprotein-associated protein) and the interaction with tudor domain-containing protein TDRD6 (By similarity). {ECO:0000250|UniProtKB:Q8CIG8, ECO:0000269|PubMed:10531356, ECO:0000269|PubMed:11152681, ECO:0000269|PubMed:11747828, ECO:0000269|PubMed:12411503, ECO:0000269|PubMed:12718890, ECO:0000269|PubMed:15737618, ECO:0000269|PubMed:17709427, ECO:0000269|PubMed:19011621, ECO:0000269|PubMed:20159986, ECO:0000269|PubMed:20421892, ECO:0000269|PubMed:20810653, ECO:0000269|PubMed:21081503, ECO:0000269|PubMed:21258366, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:22269951, ECO:0000269|PubMed:25092918, ECO:0000269|PubMed:25284789, ECO:0000269|PubMed:26700805}.

Catalytic activity: Reaction=L-arginyl-[protein] + 2 S-adenosyl-L-methionine = 2 H(+) + N(omega),N(omega)'-dimethyl-L-arginyl-[protein] + 2 S-adenosyl-L- homocysteine; Xref=Rhea:RHEA:48108, Rhea:RHEA-COMP:10532, Rhea:RHEA- COMP:11992, ChEBI:CHEBI:15378, ChEBI:CHEBI:29965, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:88221; EC=2.1.1.320; Evidence={ECO:0000269|PubMed:19011621, ECO:0000269|PubMed:21081503, ECO:0000269|PubMed:23071334};

Activity regulation: Activity is increased by EGF, HGF, FGF1 or FGF2 treatments, and slightly decreased by NGF treatment. {ECO:0000269|PubMed:21917714}.

Subunit: Forms, at least, homodimers and homotetramers (PubMed:11152681). Component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A (PubMed:21081503, PubMed:23071334, PubMed:33376131). Found in a complex composed of PRMT5, WDR77 and RIOK1 (PubMed:21081503). RIOK1 and CLNS1A associate with PRMT5 in a mutually exclusive fashion, which allows the recruitment of distinct methylation substrates, such as nucleolin/NCL and Sm proteins, respectively (PubMed:21081503). Interacts with PRDM1 (By similarity). Identified in a complex composed of methylosome and PRMT1 and ERH (PubMed:25284789). Interacts with EGFR; methylates EGFR and stimulates EGFR-mediated ERK activation. Interacts with HOXA9. Interacts with SRGAP2. Found in a complex with COPRS, RUNX1 and CBFB. Interacts with CHTOP; the interaction symmetrically methylates CHTOP, but seems to require the presence of PRMT1 (PubMed:25284789). Interacts with EPB41L3; this modulates methylation of target proteins. Component of a high molecular weight E2F-pocket protein complex, CERC (cyclin E1 repressor complex). Associates with SWI/SNF remodeling complexes containing SMARCA2 and SMARCA4. Interacts with JAK2, SSTR1, SUPT5H, BRAF and with active RAF1. Interacts with LSM11, PRMT7 and SNRPD3 (PubMed:17709427, PubMed:16087681). Interacts with COPRS; promoting its recruitment on histone H4. Interacts with CLNS1A/pICln (PubMed:21081503, PubMed:9556550). Identified in a complex with CLNS1A/pICln and Sm proteins. Interacts with RPS10 (PubMed:20159986). Interacts with WDR77. Interacts with IWS1. Interacts with CRY1. Interacts with POLR2A (PubMed:26700805). Interacts with SMN1/SMN2 (PubMed:26700805). Interacts with LYAR; this interaction is direct (PubMed:25092918). Interacts with STRAP (PubMed:19011621). Interacts with TP53 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with FAM47E; the interaction is direct, promotes PRMT5 localization to chromatin, and does not disrupt its association with WDR77 or STUB1 (PubMed:33376131). Interacts with TDRD6 (By similarity). Interacts with STUB1 (PubMed:33376131). {ECO:0000250|UniProtKB:Q8CIG8, ECO:0000269|PubMed:10531356, ECO:0000269|PubMed:10734105, ECO:0000269|PubMed:11152681, ECO:0000269|PubMed:12411503, ECO:0000269|PubMed:12718890, ECO:0000269|PubMed:15485929, ECO:0000269|PubMed:15737618, ECO:0000269|PubMed:16087681, ECO:0000269|PubMed:17184735, ECO:0000269|PubMed:17709427, ECO:0000269|PubMed:18404153, ECO:0000269|PubMed:18984161, ECO:0000269|PubMed:19011621, ECO:0000269|PubMed:20159986, ECO:0000269|PubMed:20810653, ECO:0000269|PubMed:21081503, ECO:0000269|PubMed:21258366, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:22269951, ECO:0000269|PubMed:23071334, ECO:0000269|PubMed:25092918, ECO:0000269|PubMed:25284789, ECO:0000269|PubMed:26700805, ECO:0000269|PubMed:33376131, ECO:0000269|PubMed:9556550}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:21081503, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:22269951}. Nucleus {ECO:0000269|PubMed:18404153, ECO:0000269|PubMed:21081503, ECO:0000269|PubMed:21917714, ECO:0000269|PubMed:22269951}. Chromosome {ECO:0000269|PubMed:33376131}. Golgi apparatus {ECO:0000269|PubMed:20421892}. Note=Localizes to promoter regions of target genes on chromosomes. {ECO:0000269|PubMed:33376131}.

Tissue specificity: Ubiquitous. {ECO:0000269|PubMed:9556550}.

Similarity: Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family. {ECO:0000255|PROSITE-ProRule:PRU01015}.

Sequence caution: Sequence=BC005820; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Arginine methyltransferase that can both catalyze the formation of omega-N monomethylarginine (MMA) and symmetrical dimethylarginine (sDMA), with a preference for the formation of MMA (PubMed:10531356, PubMed:11152681, PubMed:11747828, PubMed:12411503, PubMed:15737618, PubMed:17709427, PubMed:20159986, PubMed:20810653, PubMed:21258366, PubMed:21917714, PubMed:22269951, PubMed:21081503). Specifically mediates the symmetrical dimethylation of arginine residues in the small nuclear ribonucleoproteins Sm D1 (SNRPD1) and Sm D3 (SNRPD3); such methylation being required for the assembly and biogenesis of snRNP core particles (PubMed:12411503, PubMed:11747828, PubMed:17709427). Methylates SUPT5H and may regulate its transcriptional elongation properties (PubMed:12718890). Mono- and dimethylates arginine residues of myelin basic protein (MBP) in vitro. May play a role in cytokine-activated transduction pathways. Negatively regulates cyclin E1 promoter activity and cellular proliferation. Methylates histone H2A and H4 'Arg-3' during germ cell development (By similarity). Methylates histone H3 'Arg-8', which may repress transcription (By similarity). Methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage (By similarity). Methylates RPS10. Attenuates EGF signaling through the MAPK1/MAPK3 pathway acting at 2 levels. First, monomethylates EGFR; this enhances EGFR 'Tyr-1197' phosphorylation and PTPN6 recruitment, eventually leading to reduced SOS1 phosphorylation (PubMed:21917714, PubMed:21258366). Second, methylates RAF1 and probably BRAF, hence destabilizing these 2 signaling proteins and reducing their catalytic activity (PubMed:21917714). Required for induction of E-selectin and VCAM-1, on the endothelial cells surface at sites of inflammation. Methylates HOXA9 (PubMed:22269951). Methylates and regulates SRGAP2 which is involved in cell migration and differentiation (PubMed:20810653). Acts as a transcriptional corepressor in CRY1-mediated repression of the core circadian component PER1 by regulating the H4R3 dimethylation at the PER1 promoter (By similarity). Methylates GM130/GOLGA2, regulating Golgi ribbon formation (PubMed:20421892). Methylates H4R3 in genes involved in glioblastomagenesis in a CHTOP- and/or TET1-dependent manner (PubMed:25284789). Symmetrically methylates POLR2A, a modification that allows the recruitment to POLR2A of proteins including SMN1/SMN2 and SETX. This is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination (PubMed:26700805). Along with LYAR, binds the promoter of gamma-globin HBG1/HBG2 and represses its expression (PubMed:25092918). Symmetrically methylates NCL (PubMed:21081503). Methylates TP53; methylation might possibly affect TP53 target gene specificity (PubMed:19011621). Involved in spliceosome maturation and mRNA splicing in prophase I spermatocytes through the catalysis of the symmetrical arginine dimethylation of SNRPB (small nuclear ribonucleoprotein-associated protein) and the interaction with tudor domain-containing protein TDRD6 (By similarity). {ECO:0000250\|UniProtKB:Q8CIG8, ECO:0000269\|PubMed:10531356, ECO:0000269\|PubMed:11152681, ECO:0000269\|PubMed:11747828, ECO:0000269\|PubMed:12411503, ECO:0000269\|PubMed:12718890, ECO:0000269\|PubMed:15737618, ECO:0000269\|PubMed:17709427, ECO:0000269\|PubMed:19011621, ECO:0000269\|PubMed:20159986, ECO:0000269\|PubMed:20421892, ECO:0000269\|PubMed:20810653, ECO:0000269\|PubMed:21081503, ECO:0000269\|PubMed:21258366, ECO:0000269\|PubMed:21917714, ECO:0000269\|PubMed:22269951, ECO:0000269\|PubMed:25092918, ECO:0000269\|PubMed:25284789, ECO:0000269\|PubMed:26700805}.


Catalytic activity:		Reaction=L-arginyl-[protein] + 2 S-adenosyl-L-methionine = 2 H(+) + N(omega),N(omega)'-dimethyl-L-arginyl-[protein] + 2 S-adenosyl-L- homocysteine; Xref=Rhea:RHEA:48108, Rhea:RHEA-COMP:10532, Rhea:RHEA- COMP:11992, ChEBI:CHEBI:15378, ChEBI:CHEBI:29965, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:88221; EC=2.1.1.320; Evidence={ECO:0000269\|PubMed:19011621, ECO:0000269\|PubMed:21081503, ECO:0000269\|PubMed:23071334};
Activity regulation:		Activity is increased by EGF, HGF, FGF1 or FGF2 treatments, and slightly decreased by NGF treatment. {ECO:0000269\|PubMed:21917714}.
Subunit:		Forms, at least, homodimers and homotetramers (PubMed:11152681). Component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A (PubMed:21081503, PubMed:23071334, PubMed:33376131). Found in a complex composed of PRMT5, WDR77 and RIOK1 (PubMed:21081503). RIOK1 and CLNS1A associate with PRMT5 in a mutually exclusive fashion, which allows the recruitment of distinct methylation substrates, such as nucleolin/NCL and Sm proteins, respectively (PubMed:21081503). Interacts with PRDM1 (By similarity). Identified in a complex composed of methylosome and PRMT1 and ERH (PubMed:25284789). Interacts with EGFR; methylates EGFR and stimulates EGFR-mediated ERK activation. Interacts with HOXA9. Interacts with SRGAP2. Found in a complex with COPRS, RUNX1 and CBFB. Interacts with CHTOP; the interaction symmetrically methylates CHTOP, but seems to require the presence of PRMT1 (PubMed:25284789). Interacts with EPB41L3; this modulates methylation of target proteins. Component of a high molecular weight E2F-pocket protein complex, CERC (cyclin E1 repressor complex). Associates with SWI/SNF remodeling complexes containing SMARCA2 and SMARCA4. Interacts with JAK2, SSTR1, SUPT5H, BRAF and with active RAF1. Interacts with LSM11, PRMT7 and SNRPD3 (PubMed:17709427, PubMed:16087681). Interacts with COPRS; promoting its recruitment on histone H4. Interacts with CLNS1A/pICln (PubMed:21081503, PubMed:9556550). Identified in a complex with CLNS1A/pICln and Sm proteins. Interacts with RPS10 (PubMed:20159986). Interacts with WDR77. Interacts with IWS1. Interacts with CRY1. Interacts with POLR2A (PubMed:26700805). Interacts with SMN1/SMN2 (PubMed:26700805). Interacts with LYAR; this interaction is direct (PubMed:25092918). Interacts with STRAP (PubMed:19011621). Interacts with TP53 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with FAM47E; the interaction is direct, promotes PRMT5 localization to chromatin, and does not disrupt its association with WDR77 or STUB1 (PubMed:33376131). Interacts with TDRD6 (By similarity). Interacts with STUB1 (PubMed:33376131). {ECO:0000250\|UniProtKB:Q8CIG8, ECO:0000269\|PubMed:10531356, ECO:0000269\|PubMed:10734105, ECO:0000269\|PubMed:11152681, ECO:0000269\|PubMed:12411503, ECO:0000269\|PubMed:12718890, ECO:0000269\|PubMed:15485929, ECO:0000269\|PubMed:15737618, ECO:0000269\|PubMed:16087681, ECO:0000269\|PubMed:17184735, ECO:0000269\|PubMed:17709427, ECO:0000269\|PubMed:18404153, ECO:0000269\|PubMed:18984161, ECO:0000269\|PubMed:19011621, ECO:0000269\|PubMed:20159986, ECO:0000269\|PubMed:20810653, ECO:0000269\|PubMed:21081503, ECO:0000269\|PubMed:21258366, ECO:0000269\|PubMed:21917714, ECO:0000269\|PubMed:22269951, ECO:0000269\|PubMed:23071334, ECO:0000269\|PubMed:25092918, ECO:0000269\|PubMed:25284789, ECO:0000269\|PubMed:26700805, ECO:0000269\|PubMed:33376131, ECO:0000269\|PubMed:9556550}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:21081503, ECO:0000269\|PubMed:21917714, ECO:0000269\|PubMed:22269951}. Nucleus {ECO:0000269\|PubMed:18404153, ECO:0000269\|PubMed:21081503, ECO:0000269\|PubMed:21917714, ECO:0000269\|PubMed:22269951}. Chromosome {ECO:0000269\|PubMed:33376131}. Golgi apparatus {ECO:0000269\|PubMed:20421892}. Note=Localizes to promoter regions of target genes on chromosomes. {ECO:0000269\|PubMed:33376131}.
Tissue specificity:		Ubiquitous. {ECO:0000269\|PubMed:9556550}.
Similarity:		Belongs to the class I-like SAM-binding methyltransferase superfamily. Protein arginine N-methyltransferase family. {ECO:0000255\|PROSITE-ProRule:PRU01015}.
Sequence caution:		Sequence=BC005820; Type=Frameshift; Evidence={ECO:0000305};