PT - JOURNAL ARTICLE AU - Christopher M. Bartley AU - Rachel A. O’Keefe AU - Anna Blice-Baum AU - Mihaela-Rita Mihailescu AU - Xuan Gong AU - Laura Miyares AU - Esra Karaca AU - Angélique Bordey TI - Mammalian FMRP S499 is phosphorylated by CK2 and promotes secondary phosphorylation of FMRP AID - 10.1523/ENEURO.0092-16.2016 DP - 2016 Nov 01 TA - eneuro PG - ENEURO.0092-16.2016 4099 - http://www.eneuro.org/content/early/2016/11/01/ENEURO.0092-16.2016.short 4100 - http://www.eneuro.org/content/early/2016/11/01/ENEURO.0092-16.2016.full AB - 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 (CK) 2 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 phospho-dynamic model of FMRP that is harmonious with prior studies and serves as a framework for further investigation.Significance StatementFMRP’s role in translation and plasticity is dependent on the phosphorylation status of serine 499, however, the kinase phosphorylating FMRP remains unknown in mammals. Here, we identified that a constitutively active kinase, CK2, phosphorylates mammalian FMRP S499. In addition, S499 phosphorylation allows phosphorylation of additional, nearby residues that are likely modulated downstream of metabotropic glutamate signaling in an activity-dependent manner. This finding provides an explanation for how FMRP S499 contributes to activity-dependent FMRP function without itself being modulated by activity.