PT - JOURNAL ARTICLE AU - Yoshiki Kobayashi AU - Anna Miller-Larsson AU - Kazuhiro Ito AU - Akira Kanda AU - Koichi Tomoda AU - Peter J. Barnes AU - Nicolas Mercado TI - Protein tyrosine phosphatase PTPRR regulates PP2A in mononuclear cells DP - 2014 Sep 01 TA - European Respiratory Journal PG - P1467 VI - 44 IP - Suppl 58 4099 - http://erj.ersjournals.com/content/44/Suppl_58/P1467.short 4100 - http://erj.ersjournals.com/content/44/Suppl_58/P1467.full SO - Eur Respir J2014 Sep 01; 44 AB - Introduction: We have recently found that impaired protein tyrosine phosphatase PTPRR and serine/threonine phosphatase PP2A expression and activity lead to lower dephosphorylation of glucocorticoid receptor (GR)-Ser226 via c-Jun N-terminal kinase 1 (JNK1), and to lower nuclear translocation of GR, resulting in corticosteroid insensitivity.Aims: To elucidate the association between PTPRR and PP2A in regulation of corticosteroid sensitivity.Methods: Protein expression of PTPRR and PP2A catalytic subunit (PP2AC) and phosphorylation levels of PP2AC-Tyr307 were evaluated by Western-Blot in monocytic U937 cell line or peripheral blood mononuclear cells (PBMCs). Effects of PTPRR and PP2A knock down using siRNA were evaluated in U937 cells. Phosphatase activities of immunopurified PTPRR and PP2AC were analyzed by fluorescence-based assay.Results: In PBMCs from severe asthmatics, PTPRR and PP2AC expression were reduced and positively correlated to each other. PTPRR was associated with PP2AC in the cytoplasm. PTPRR reduction attenuated PP2AC expression and activity with concomitant enhancement of PP2AC-Tyr307 phosphorylation whereas PP2A reduction did not alter PTPRR expression or activity. In addition, PTPRR expression positively correlated with PP2AC-Tyr307 phosphorylation and negatively with PP2AC activity. Interestingly, PTPRR was activated by formoterol, independently of β2adrenoceptor.Conclusion: We have demonstrated that reduction of PTPRR down-regulates PP2AC via enhancement of PP2AC-Tyr307 phosphorylation that may lead to corticosteroid insensitivity. This novel mechanism may be a new therapeutic target for restoration of corticosteroid sensitivity in patients with severe asthma.