title: Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia.
abstract: Neuropathology of resected brain tissue has revealed an association of focal cortical dysplasia (FCD) with drug-resistant epilepsy (DRE). Recent studies have shown that the mechanistic target of rapamycin (mTOR) pathway is hyperactivated in FCD as evidenced by increased phosphorylation of the ribosomal protein S6 (S6) at serine 240/244 (S(240/244) ), a downstream target of mTOR. Moreover, extracellular regulated kinase (ERK) has been shown to phosphorylate S6 at serine 235/236 (S(235/236) ) and tuberous sclerosis complex 2 (TSC2) at serine 664 (S(664) ) leading to hyperactive mTOR signaling. We evaluated ERK phosphorylation of S6 and TSC2 in two types of FCD (FCD I and FCD II) as a candidate mechanism contributing to mTOR pathway dysregulation. Tissue samples from patients with tuberous sclerosis (TS) served as a positive control. Immunostaining for phospho-S6 (pS6(240/244) and pS6(235/236) ), phospho-ERK (pERK), and phospho-TSC2 (pTSC2) was performed on resected brain tissue with FCD and TS. We found increased pS6(240/244) and pS6(235/236) staining in FCD I, FCD II and TS compared to normal-appearing tissue, while pERK and pTSC2 staining was increased only in FCD IIb and TS tissue. Our results suggest that both the ERK and mTOR pathways are dysregulated in FCD and TS; however, the signaling alterations are different for FCD I as compared to FCD II and TS.
authors.affiliation: Program in Translational Biology and Molecular Medicine, Texas Children's Hospital, Houston, Texas, USA.|Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.|Department of Pathology, Saint Louis University, Saint Louis, Missouri.
authors.forename: Vinit V
authors.initials: VV
authors.lastname: Patil
authors.affiliation: Department of Pathology, Saint Louis University, Saint Louis, Missouri.
authors.forename: Miguel
authors.initials: M
authors.lastname: Guzman
authors.affiliation: Department of Neuroscience, Texas Children's Hospital, Houston, Texas, USA.|Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Angela N
authors.initials: AN
authors.lastname: Carter
authors.affiliation: Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Rathore
authors.affiliation: Department of Neurosurgery, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yoshor
authors.affiliation: Department of Neurosurgery, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Curry
authors.affiliation: Department of Neurology, Texas Children's Hospital, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Angus
authors.initials: A
authors.lastname: Wilfong
authors.affiliation: Department of Neurology, Texas Children's Hospital, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Agadi
authors.affiliation: Department of Neuroscience, Texas Children's Hospital, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.|Program in Translational Biology and Molecular Medicine, Texas Children's Hospital, Houston, Texas, USA.|Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Swann
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Medical School, Houston, Texas, USA.
authors.forename: Meenakshi B
authors.initials: MB
authors.lastname: Bhattacharjee
authors.affiliation: Department of Neurology, Texas Children's Hospital, Houston, Texas, USA.|Department of Neuroscience, Texas Children's Hospital, Houston, Texas, USA.|Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA.|Program in Translational Biology and Molecular Medicine, Texas Children's Hospital, Houston, Texas, USA.|Cain Foundation Laboratories, Texas Children's Hospital, Houston, Texas, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Anderson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D004827:Epilepsy / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D020935:MAP Kinase Signaling System / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008297:Male; D065703:Malformations of Cortical Development, Group I / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D038601:Ribosomal Protein S6 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D038601:Ribosomal Protein S6; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Drug-resistant epilepsy (DRE); Extracellular regulated kinase (ERK); focal cortical dysplasia (FCD); mechanistic target of rapamycin (mTOR); tuberous sclerosis (TS)