title: FMRP S499 is phosphorylated independent of mTORC1-S6K1 activity.
abstract: Hyperactive mammalian target of rapamycin (mTOR) is associated with cognitive deficits in several neurological disorders including tuberous sclerosis complex (TSC). The phosphorylation of the mRNA-binding protein FMRP reportedly depends on mTOR complex 1 (mTORC1) activity via p70 S6 kinase 1 (S6K1). Because this phosphorylation is thought to regulate the translation of messages important for synaptic plasticity, we explored whether FMRP phosphorylation of the S6K1-dependent residue (S499) is altered in TSC and states of dysregulated TSC-mTORC1 signaling. Surprisingly, we found that FMRP S499 phosphorylation was unchanged in heterozygous and conditional Tsc1 knockout mice despite significantly elevated mTORC1-S6K1 activity. Neither up- nor down-regulation of the mTORC1-S6K1 axis in vivo or in vitro had any effect on phospho-FMRP S499 levels. In addition, FMRP S499 phosphorylation was unaltered in S6K1-knockout mice. Collectively, these data strongly suggest that FMRP S499 phosphorylation is independent of mTORC1-S6K1 activity and is not altered in TSC.
authors.affiliation: Departments 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.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bartley
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: O'Keefe
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Angélique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D000818:Animals; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics; D010766:Phosphorylation; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; C497684:Fmr1 protein, mouse; C512964:Rps6ka1 protein, mouse