Protein tyrosine phosphatase PTPRR regulates PP2A in mononuclear cells

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)-Ser 226 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 (PP2A C ) and phosphorylation levels of PP2A C -Tyr 307 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 PP2A C were analyzed by fluorescence-based assay. Results: In PBMCs from severe asthmatics, PTPRR and PP2A C expression were reduced and positively correlated to each other. PTPRR was associated with PP2A C in the cytoplasm. PTPRR reduction attenuated PP2A C expression and activity with concomitant enhancement of PP2A C -Tyr 307 phosphorylation whereas PP2A reduction did not alter PTPRR expression or activity. In addition, PTPRR expression positively correlated with PP2A C -Tyr 307 phosphorylation and negatively with PP2A C activity. Interestingly, PTPRR was activated by formoterol, independently of β 2 adrenoceptor. Conclusion: We have demonstrated that reduction of PTPRR down-regulates PP2A C via enhancement of PP2A C -Tyr 307 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.