title: Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1.
abstract: Multiple protein arginine methyltransferases are involved in transcriptional activation of nuclear receptors. Coactivator-associated arginine methyltransferase 1 (CARM1)-mediated histone methylation has been shown to activate nuclear receptor-dependent transcription; however, little is known about the regulation of its enzymatic activity. Here, we report that the methyltransferase activity of CARM1 is negatively regulated through phosphorylation at a conserved serine residue. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. Moreover, such mutation leads to the inhibition of CARM1 transactivation of estrogen receptor-dependent transcription. Our results provide an example for the regulation of protein arginine methyltransferase activity by phosphorylation. As CARM1 is a potent transcriptional coactivator of estrogen receptor, our results suggest that phosphorylation of CARM1 serves as a unique mechanism for inactivating CARM1-regulated estrogen-dependent gene expression.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin, 1400 University Avenue, Madison, WI 53706, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Higashimoto
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
authors.forename: Dhaval
authors.initials: D
authors.lastname: Desai
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D017124:Conserved Sequence; D019281:Dimerization; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008938:Mitosis; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D016415:Sequence Alignment; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D011960:Receptors, Estrogen; D012694:Serine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1