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

Christopher M Bartley1, Rachel A O'Keefe2, Anna Blice-Baum3

  • 1Departments 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.

Eneuro
|December 14, 2016
PubMed

Insights

Casein kinase II (CK2) phosphorylates fragile X mental retardation protein (FMRP) at serine 499. This phosphorylation allows further modifications, offering a new model for FMRP regulation in neurodevelopment and autism.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Fragile X mental retardation protein (FMRP) regulates translation of brain transcripts and is crucial for neurodevelopment.
  • FMRP loss-of-function causes fragile X syndrome, a leading cause of monogenetic autism, with its transcripts enriched in autism risk genes.
  • FMRP-dependent translational repression is hypothesized to be controlled by serine 499 (S499) phosphorylation, though its regulation is debated.

Purpose of the Study:

  • To identify the mammalian kinase responsible for FMRP S499 phosphorylation.
  • To investigate the role of S499 phosphorylation in FMRP regulation.
  • To propose an alternative phosphodynamic model for FMRP function.

Main Methods:

  • Biochemical assays to identify FMRP kinase activity.
  • Phosphorylation site mapping of FMRP.
  • Investigating the interplay between S499 phosphorylation and other regulatory pathways.

Main Results:

  • Casein kinase II (CK2) was identified as the kinase phosphorylating murine FMRP at S499.
  • Phosphorylation of FMRP S499 was shown to enable subsequent phosphorylation of nearby residues.
  • These additional phosphorylation sites appear to be modulated by metabotropic glutamate receptor I (mGluR-I) and protein phosphatase 2A (PP2A) pathways.

Conclusions:

  • CK2 is the mammalian kinase for FMRP S499 phosphorylation.
  • An alternative phosphodynamic model for FMRP regulation is proposed, integrating previous findings.
  • This model provides a framework for understanding FMRP's role in neurodevelopment and autism.
Keywords:
FMRPcasein kinasefragile XmTORphosphorylationtranslation

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