Mammalian FMRP S499 Is Phosphorylated by CK2 and Promotes Secondary Phosphorylation of FMRP

eNeuro. 2016 Nov 21;3(6):ENEURO.0092-16.2016. doi: 10.1523/ENEURO.0092-16.2016. eCollection 2016 Nov-Dec.

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.

Keywords: FMRP; casein kinase; fragile X; mTOR; phosphorylation; translation.

MeSH terms

  • Animals
  • Blotting, Western
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • HEK293 Cells
  • Humans
  • Mass Spectrometry
  • Mice
  • Naphthyridines / pharmacology
  • Phenazines
  • Phosphorylation / drug effects
  • Phosphorylation / physiology
  • Protein Biosynthesis
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Metabotropic Glutamate / metabolism
  • Recombinant Proteins / metabolism
  • Time Factors

Substances

  • FMR1 protein, human
  • Fmr1 protein, mouse
  • Naphthyridines
  • Phenazines
  • Protein Kinase Inhibitors
  • Receptors, Metabotropic Glutamate
  • Recombinant Proteins
  • metabotropic glutamate receptor type 1
  • Fragile X Mental Retardation Protein
  • silmitasertib
  • Casein Kinase II