Woetmann Anders, Brockdorff Johannes, Lovato Paola, Nielsen Mette, Leick Vagn, Rieneck Klaus, Svejgaard Arne, Geisler Carsten, Ødum Niels
Institute of Medical Microbiology and Immunology, University of Copenhagen, DK2200 Copenhagen, Denmark.
J Biol Chem. 2003 Jan 31;278(5):2787-91. doi: 10.1074/jbc.M210196200. Epub 2002 Nov 7.
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.
白细胞介素-4（IL-4）通过促进Th2分化和B细胞向IgE的同种型转换，在过敏反应的诱导和维持中起关键作用。对STAT6缺陷小鼠的研究表明STAT6在介导IL-4的生物学功能中起重要作用。IL-4诱导STAT6的酪氨酸磷酸化，进而导致IL-4特异性基因的转录。此外，最近报道了STAT6的丝氨酸磷酸化。在此，我们研究STAT6丝氨酸磷酸化的功能作用以及相关的激酶和磷酸酶。我们发现抑制蛋白磷酸酶2A（PP2A）可诱导STAT6的丝氨酸磷酸化，并严重抑制STAT6与DNA的结合。相反，IL-4诱导的Janus激酶-1和STAT6的酪氨酸磷酸化不受影响，这表明PP2A在IL-4信号传导中作用于Janus激酶的下游。总之，我们首次提供证据表明PP2A在STAT6功能调节中起关键作用。
