title: Epidermal growth factor receptor (EGFR) involvement in successful growth hormone (GH) signaling in GH transduction defect.
abstract: BACKGROUND
  Growth hormone (GH) transduction defect (GHTD) is a growth disorder with impaired signal transducer and activator of transcription 3 (STAT3) phosphorylation mediated by overexpression of cytokine-inducible SH2-containing protein (CIS), which causes increased growth hormone receptor (GHR) degradation. This study investigated the role of epidermal growth factor (EGF) in the restoration of normal GH signaling in GHTD.
  
  
  METHODS
  Protein expression, cellular localization and physical contact of proteins of the GH and EGF signaling pathways were studied by Western immunoblotting, immunofluorescence and co-immunoprecipitation, respectively. These were performed in fibroblasts of one GHTD patient (P) and one control child (C) at the basal state and after induction with human GH (hGH) 200 μg/L (GH200), either with or without silencing of CIS mRNA, and after induction with hGH 1000 μg/L (GH1000) or 50 ng/mL EGF.
  
  
  RESULTS
  The membrane availability of the EGF receptor (EGFR) and the activated EGFR (pEGFR) was increased in P only after simultaneous GH200 and silencing of CIS mRNA or with GH1000, whereas this occurred in C after GH200 alone. After EGF induction, the membrane localization of GHR, STAT3 and that of EGFR were increased in P more than in C.
  
  
  CONCLUSIONS
  In conclusion, in GHTD, the EGFR seems to participate in successful GH signaling, but induction of GHTD fibroblasts with a higher dose of hGH is needed. The EGF/EGFR pathway, in contrast to the GH/GHR pathway, seems to function normally in P and is more primed compared to C. The involvement of the EGFR in successful GH signaling may explain the catch-up growth seen in the Ps when exogenous hGH is administered.
authors.forename: Eirini
authors.initials: E
authors.lastname: Kostopoulou
authors.forename: Andrea Paola
authors.initials: AP
authors.lastname: Rojas-Gil
authors.forename: Alexia
authors.initials: A
authors.lastname: Karvela
authors.forename: Bessie E
authors.initials: BE
authors.lastname: Spiliotis
mesh_terms: D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D002648:Child; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006130:Growth Disorders / Q000503:physiopathology*; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D011986:Receptors, Somatotropin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019382:Human Growth Hormone; D011986:Receptors, Somatotropin; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; C512478:EGFR protein, human