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FMRP S499 is phosphorylated independent of mTORC1-S6K1 activity

Christopher M Bartley1, Rachel A O'Keefe2, Angélique Bordey2

  • 1Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States of America; Medical Scientist Training Program, Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

Plos One
|May 9, 2014
PubMed

Insights

mTORC1-S6K1 signaling does not alter FMRP S499 phosphorylation in tuberous sclerosis complex (TSC). This finding suggests FMRP phosphorylation is independent of mTORC1-S6K1 activity in neurological disorders.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Hyperactive mammalian target of rapamycin (mTOR) signaling is linked to cognitive impairments in neurological disorders like tuberous sclerosis complex (TSC).
  • The mRNA-binding protein FMRP's phosphorylation, regulated by mTOR complex 1 (mTORC1) via p70 S6 kinase 1 (S6K1), is crucial for synaptic plasticity.
  • Dysregulated mTORC1-S6K1 signaling may affect FMRP phosphorylation at the S6K1-dependent residue (S499) in TSC.

Purpose of the Study:

  • To investigate whether FMRP S499 phosphorylation is altered in tuberous sclerosis complex (TSC).
  • To determine the relationship between dysregulated TSC-mTORC1 signaling and FMRP S499 phosphorylation.
  • To examine the role of the mTORC1-S6K1 axis in regulating FMRP S499 phosphorylation in vivo and in vitro.

Main Methods:

  • Utilized heterozygous and conditional Tsc1 knockout mouse models to study TSC and mTORC1-S6K1 activity.
  • Manipulated mTORC1-S6K1 axis activity in vivo and in vitro.
  • Analyzed FMRP S499 phosphorylation levels in wild-type, knockout, and manipulated cellular and animal models.
  • Examined FMRP S499 phosphorylation in S6K1-knockout mice.

Main Results:

  • FMRP S499 phosphorylation remained unchanged in Tsc1 knockout mice despite elevated mTORC1-S6K1 activity.
  • Modulating mTORC1-S6K1 activity, either up or down, did not affect FMRP S499 phosphorylation levels.
  • FMRP S499 phosphorylation was unaltered in mice lacking S6K1.
  • These findings indicate FMRP S499 phosphorylation is independent of mTORC1-S6K1 activity.

Conclusions:

  • FMRP S499 phosphorylation is independent of mTORC1-S6K1 signaling.
  • FMRP S499 phosphorylation is not altered in the context of tuberous sclerosis complex (TSC).
  • The study challenges the presumed link between mTORC1-S6K1 activity and FMRP S499 phosphorylation in neurological disorders.

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