title: Mammalian FMRP S499 Is Phosphorylated by CK2 and Promotes Secondary Phosphorylation of FMRP.
abstract: The fragile X mental retardation protein (FMRP) is an mRNA-binding regulator of protein translation that associates with 4-6% of brain transcripts and is central to neurodevelopment. Autism risk genes' transcripts are overrepresented among FMRP-binding mRNAs, and FMRP loss-of-function mutations are responsible for fragile X syndrome, the most common cause of monogenetic autism. It is thought that FMRP-dependent translational repression is governed by the phosphorylation of serine residue 499 (S499). However, recent evidence suggests that S499 phosphorylation is not modulated by metabotropic glutamate receptor class I (mGluR-I) or protein phosphatase 2A (PP2A), two molecules shown to regulate FMRP translational repression. Moreover, the mammalian FMRP S499 kinase remains unknown. We found that casein kinase II (CK2) phosphorylates murine FMRP S499. Further, we show that phosphorylation of FMRP S499 permits phosphorylation of additional, nearby residues. Evidence suggests that these nearby residues are modulated by mGluR-I and PP2A pathways. These data support an alternative phosphodynamic model of FMRP that is harmonious with prior studies and serves as a framework for further investigation.
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Christopher M
authors.identifier: 0000-0002-1391-4130
authors.initials: CM
authors.lastname: Bartley
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT 06510.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: O'Keefe
authors.affiliation: Department of Chemistry and Biochemistry, Duquesne University , Pittsburgh, PA 15282.
authors.forename: Anna
authors.initials: A
authors.lastname: Blice-Baum
authors.affiliation: Department of Chemistry and Biochemistry, Duquesne University , Pittsburgh, PA 15282.
authors.forename: Mihaela-Rita
authors.identifier: 0000-0002-1162-7699
authors.initials: MR
authors.lastname: Mihailescu
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Gong
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT 06510.
authors.forename: Laura
authors.identifier: 0000-0002-1698-6199
authors.initials: L
authors.lastname: Miyares
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT 06510.
authors.forename: Esra
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT 06510.
authors.forename: Angélique
authors.identifier: 0000-0003-3496-3385
authors.initials: A
authors.lastname: Bordey
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D010619:Phenazines; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: D047390:Casein Kinase II; D051860:Fragile X Messenger Ribonucleoprotein 1; D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse; C104077:metabotropic glutamate receptor type 1; C555142:silmitasertib
keywords: FMRP; casein kinase; fragile X; mTOR; phosphorylation; translation