title: A novel SOS1 mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways.
abstract: BACKGROUND
  Pathological upregulation of the RAS/MAPK pathway causes Costello, Noonan and cardio-facio-cutaneous (CFC) syndrome; however, little is known about PI3K/AKT signal transduction in these syndromes. Previously, we found a novel mutation of the SOS1 gene (T158A) in a patient with Costello/CFC overlapping phenotype.
  
  
  OBJECTIVE
  The aim of this study was to investigate how this mutation affects RAS/MAPK as well as PI3K/AKT pathway signal transduction.
  
  
  METHODS
  Wild-type and mutant (T158A) Son of Sevenless 1 (SOS1) were transfected into 293T cells. The levels of phospho- and total ERK1/2, AKT, p70S6K and pS6 were examined under epidermal growth factor (EGF) stimulation.
  
  
  RESULTS
  After EGF stimulation, the ratio of phospho-ERK1/2 to total ERK1/2 was highest at 5 min in mutant (T158A) SOS1 cells, and at 15 min in wild-type SOS1 cells. Phospho-AKT was less abundant at 60 min in mutant than in wild-type SOS1 cells. Phosphorylation at various sites in p70S6K differed between wild-type and mutant cells. Eighteen hours after activation by EGF, the ratio of phospho-ERK1/2 to total ERK1/2 remained significantly higher in mutant than in wild-type SOS1 cells, but that of phospho-AKT to total AKT was unchanged.
  
  
  CONCLUSIONS
  T158A is located in the histone-like domain, which may have a role in auto-inhibition of RAS exchanger activity of SOS1. T158A may disrupt auto-inhibition and enhance RAS signaling. T158A also affects PI3K/AKT signaling, probably via negative feedback via phospho-p70S6K.
  
  
  CONCLUSIONS
  The SOS1 T158A mutation altered the phosphorylation of gene products involved in both RAS/MAPK and PI3K/AKT pathways.
authors.affiliation: Department of Developmental Medical Sciences, Institute of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Munkhtuya
authors.initials: M
authors.lastname: Tumurkhuu
authors.forename: Makiko
authors.initials: M
authors.lastname: Saitoh
authors.forename: Junko
authors.initials: J
authors.lastname: Takita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizuguchi
mesh_terms: D056685:Costello Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D020837:SOS1 Protein / Q000235:genetics*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020837:SOS1 Protein; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D018631:ras Proteins