title: PRMT5 C-terminal Phosphorylation Modulates a 14-3-3/PDZ Interaction Switch.
abstract: PRMT5 is the primary enzyme responsible for the deposition of the symmetric dimethylarginine in mammalian cells. In an effort to understand how PRMT5 is regulated, we identified a threonine phosphorylation site within a C-terminal tail motif, which is targeted by the Akt/serum- and glucocorticoid-inducible kinases. While investigating the function of this posttranslational modification, we serendipitously discovered that its free C-terminal tail binds PDZ domains (when unphosphorylated) and 14-3-3 proteins (when phosphorylated). In essence, a phosphorylation event within the last few residues of the C-terminal tail generates a posttranslational modification-dependent PDZ/14-3-3 interaction "switch." The C-terminal motif of PRMT5 is required for plasma membrane association, and loss of this switching capacity is not compatible with life. This signaling phenomenon was recently reported for the HPV E6 oncoprotein but has not yet been observed for mammalian proteins. To investigate the prevalence of PDZ/14-3-3 switching in signal transduction, we built a protein domain microarray that harbors PDZ domains and 14-3-3 proteins. We have used this microarray to interrogate the C-terminal tails of a small group of candidate proteins and identified ERBB4, PGHS2, and IRK1 (as well as E6 and PRMT5) as conforming to this signaling mode, suggesting that PDZ/14-3-3 switching may be a broad biological paradigm.
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.|the University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Alexsandra B
authors.identifier: 0000-0002-8841-7219
authors.initials: AB
authors.lastname: Espejo
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Gao
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Karynne
authors.initials: K
authors.lastname: Black
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.|the University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Sitaram
authors.initials: S
authors.lastname: Gayatri
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.|the University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Veland
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Jeesun
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.affiliation: the Department of Physiology, National University of Singapore, Mechanobiology Institute and Institute for Molecular and Cell Biology (IMCB, A*STAR), Singapore 117597, Singapore, and.
authors.forename: Marius
authors.identifier: 0000-0003-3051-6406
authors.initials: M
authors.lastname: Sudol
authors.affiliation: the Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas 77030.
authors.forename: Cheryl
authors.identifier: 0000-0003-4854-9695
authors.initials: C
authors.lastname: Walker
authors.affiliation: From the Department of Epigenetics and Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville, Texas 78957, mtbedford@mdanderson.org.
authors.forename: Mark T
authors.identifier: 0000-0002-8899-1050
authors.initials: MT
authors.lastname: Bedford
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D051379:Mice; D054731:PDZ Domains; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: 14–3-3 protein; PDZ domain; cell signaling; protein arginine N-methyltransferase 5 (PRMT5); protein methylation; protein phosphorylation