title: Protein tyrosine phosphatase PTP-RR regulates corticosteroid sensitivity.
abstract: BACKGROUND
  We have recently reported that protein phosphate 2A (PP2A) inactivation resulted in increased phosphorylation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase 1 (JNK1) and glucocorticoid receptors (GR) at Ser(226), thereby reducing GR nuclear translocation and causing corticosteroid insensitivity in severe asthmatics. Protein tyrosine phosphatases (PTPs) are also known to be critically involved in the regulation of MAPKs, such as JNK and therefore potentially associated with GR function. The aim of study was to elucidate the involvement of MAPK-PTPs (PTP-RR, PTP-N5 and PTP-N7), which can dephosphorylate MAPKs, in the regulation of corticosteroid sensitivity.
  
  
  METHODS
  Corticosteroid sensitivity, GR nuclear translocation, phosphorylation levels of GR-Ser(226), JNK1 and PP2A catalytic subunit (PP2AC)-Tyr(307) and protein expression levels and activities of PTP-RR and PP2AC were evaluated in U937 cells and/or peripheral blood mononuclear cells (PBMCs). Knock-down effects of MAPK-PTPs using siRNA were also evaluated.
  
  
  RESULTS
  Knock-down of PTP-RR, but not of PTP-N5 or PTP-N7 impaired corticosteroid sensitivity, induced GR-Ser(226) phosphorylation and reduced GR nuclear translocation. Under IL-2/IL-4-induced corticosteroid insensitivity, PTP-RR expression, activity and associations with JNK1 and GR were reduced but PTP-RR activity was restored by formoterol. Also in PBMCs from severe asthmatic patients, PTP-RR and JNK1 expression were reduced and GR-Ser(226) phosphorylation increased. Furthermore, PTP-RR was associated with PP2A. PTP-RR reduction enhanced PP2AC-Tyr(307) phosphorylation leading to impairment of PP2A expression and activity.
  
  
  CONCLUSIONS
  We demonstrated that with corticosteroid insensitivity PTP-RR fails to reduce phosphorylation of JNK1 and GR-Ser(226), resulting in down-regulation of GR nuclear translocation. Reduced PTP-RR may represent a novel cause of corticosteroid insensitivity in severe asthmatics.
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Royal Brompton Campus, Dovehouse Street, London, SW3 6LY, UK. kobayosh@hirakata.kmu.ac.jp.|Airway Medicine, Department of Otolaryngology, Kansai Medical University, Osaka, Japan. kobayosh@hirakata.kmu.ac.jp.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Royal Brompton Campus, Dovehouse Street, London, SW3 6LY, UK.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
authors.affiliation: Airway Medicine, Department of Otolaryngology, Kansai Medical University, Osaka, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kanda
authors.affiliation: Airway Medicine, Department of Otolaryngology, Kansai Medical University, Osaka, Japan.
authors.forename: Koich
authors.initials: K
authors.lastname: Tomoda
authors.affiliation: AstraZeneca R&D Mölndal, Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Miller-Larsson
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Royal Brompton Campus, Dovehouse Street, London, SW3 6LY, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Airway Disease Section, National Heart and Lung Institute, Imperial College London, Guy Scadding Building, Royal Brompton Campus, Dovehouse Street, London, SW3 6LY, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mercado
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D018927:Anti-Asthmatic Agents; D011965:Receptors, Glucocorticoid; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases
keywords: Corticosteroid insensitivity; Glucocorticoid receptor; PP2A; PTP-RR; Severe asthma