Gómez del Arco P, Martínez-Martínez S, Maldonado J L, Ortega-Pérez I, Redondo J M
Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas-Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, Madrid 28049, Spain.
J Biol Chem. 2000 May 5;275(18):13872-8. doi: 10.1074/jbc.275.18.13872.
Calcium signals lead to the translocation of nuclear factor of activated T cells (NFAT) from the cytoplasm to the nucleus. This process is regulated by the calcium-activated phosphatase calcineurin, which can be cotransported with NFAT to the nucleus to maintain it transcriptionally active for the duration of calcium signaling. When the calcium signal ceases, NFAT is exported to the cytoplasm, and different NFAT kinases have been reported to oppose calcineurin activities and regulate the nuclear export of NFAT. Here we show that p38 MAPK phosphorylates in vitro and interacts in vivo with NFATp. Furthermore, the activation of this pathway in HeLa cells by cotransfection with activated MKK6 and p38 counteracts the calcium-induced nuclear accumulation of NFATp but not that of NFATc. By contrast, activation of JNK or ERK pathways failed to modify the nuclear shuttling of NFATp. Consistently, activation of p38, but not the JNK MAPK pathway, results in the inhibition of NFATp-driven transcription. In addition, the inhibition of the nuclear accumulation of NFATp by p38 appears to be mediated through the activation of NFATp nuclear export and takes place in a Leptomycin B-sensitive fashion, suggesting the involvement of the exportin CRM1 in this process. Thus, the p38 signal transduction pathway appears to play an important role in the regulation of the nuclear shuttling of NFATp and in cellular homeostasis.
钙信号导致活化T细胞核因子（NFAT）从细胞质转移至细胞核。这一过程受钙激活磷酸酶钙调神经磷酸酶调控，该酶可与NFAT共同转运至细胞核，在钙信号持续期间维持其转录活性。当钙信号终止时，NFAT被输出至细胞质，据报道不同的NFAT激酶可对抗钙调神经磷酸酶的活性并调节NFAT的核输出。在此我们表明，p38丝裂原活化蛋白激酶（MAPK）在体外使NFATp磷酸化并在体内与NFATp相互作用。此外，通过与活化的MKK6和p38共转染在HeLa细胞中激活该信号通路可抵消钙诱导的NFATp核内积累，但对NFATc的核内积累无此作用。相比之下，JNK或ERK信号通路的激活未能改变NFATp的核穿梭。一致地，p38的激活而非JNK MAPK信号通路可导致NFATp驱动的转录受到抑制。此外，p38对NFATp核内积累的抑制似乎是通过激活NFATp的核输出介导的，且以对雷帕霉素B敏感的方式发生，提示输出蛋白CRM1参与了这一过程。因此，p38信号转导通路似乎在调节NFATp的核穿梭及细胞稳态中发挥重要作用。
