title: Myosin phosphatase and RhoA-activated kinase modulate arginine methylation by the regulation of protein arginine methyltransferase 5 in hepatocellular carcinoma cells.
abstract: Myosin phosphatase (MP) holoenzyme is a protein phosphatase-1 (PP1) type Ser/Thr specific enzyme that consists of a PP1 catalytic (PP1c) and a myosin phosphatase target subunit-1 (MYPT1). MYPT1 is an ubiquitously expressed isoform and it targets PP1c to its substrates. We identified the protein arginine methyltransferase 5 (PRMT5) enzyme of the methylosome complex as a MYPT1-binding protein uncovering the nuclear MYPT1-interactome of hepatocellular carcinoma cells. It is shown that PRMT5 is regulated by phosphorylation at Thr80 by RhoA-associated protein kinase and MP. Silencing of MYPT1 increased the level of the PRMT5-specific symmetric dimethylation on arginine residues of histone 2 A/4, a repressing gene expression mark, and it resulted in a global change in the expression of genes affecting cellular processes like growth, proliferation and cell death, also affecting the expression of the retinoblastoma protein and c-Myc. The phosphorylation of the MP inhibitory MYPT1T850and the regulatory PRMT5T80residues as well as the symmetric dimethylation of H2A/4 were elevated in human hepatocellular carcinoma and in other types of cancers. These changes correlated positively with the grade and state of the tumors. Our results suggest the tumor suppressor role of MP via inhibition of PRMT5 thereby regulating gene expression through histone arginine dimethylation.
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Sipos
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.|MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Iván
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.|MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Bálint
authors.initials: B
authors.lastname: Bécsi
authors.affiliation: Laboratory of Proteomics Research, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6726, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Darula
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Tamás
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Dániel
authors.initials: D
authors.lastname: Horváth
authors.affiliation: Laboratory of Proteomics Research, Biological Research Centre, Hungarian Academy of Sciences, Szeged, H-6726, Hungary.
authors.forename: Katalin F
authors.initials: KF
authors.lastname: Medzihradszky
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.|MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Erdődi
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Lontay
mesh_terms: D001120:Arginine / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008745:Methylation; D008954:Models, Biological; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D013379:Substrate Specificity; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D010769:Phosphothreonine; D001120:Arginine; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase