Protein phosphatase 2A (PP2A) regulates interleukin-4-mediated STAT6 signaling.
Interleukin-4 (IL-4) plays a pivotal role in the induction and maintenance of allergy by promoting Th2 differentiation and B cell isotype switching to IgE. Studies on STAT6-deficient mice have demonstrated the essential role of STAT6 in mediating the biological functions of IL-4. IL-4 induces tyrosine phosphorylation of STAT6, which in turn leads to transcription of IL-4-specific genes. In addition, serine phosphorylation of STAT6 has recently been reported. Here we study the functional role of STAT6 serine phosphorylation and the kinases and phosphatases involved. We show that inhibition of protein phosphatase 2A (PP2A) induces serine phosphorylation of STAT6 and severely inhibits DNA binding of STAT6. In contrast, IL-4-induced tyrosine phosphorylation of Janus kinase-1 and STAT6 is not affected, suggesting that PP2A acts downstream of Janus kinases in IL-4 signaling. In conclusion, we provide the first evidence that PP2A plays a crucial role in the regulation of STAT6 function.
Woetmann
Anders
A
Institute of Medical Microbiology and Immunology, University of Copenhagen, DK2200 Copenhagen, Denmark.
Brockdorff
Johannes
J
Lovato
Paola
P
Nielsen
Mette
M
Leick
Vagn
V
Rieneck
Klaus
K
Svejgaard
Arne
A
Geisler
Carsten
C
Ødum
Niels
N
D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000502:physiology*; D019169:Jurkat Cells; D008387:Marine Toxins; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054648:Protein Phosphatase 2; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection
D004791:Enzyme Inhibitors; D008387:Marine Toxins; D009838:Oligodeoxyribonucleotides; D010080:Oxazoles; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D015847:Interleukin-4; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D019311:Staurosporine