A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp

Calcium signals lead to the translocation of nuclear factor of activated T cells (NFAT) from the cytoplasm to the nucleus. This process is regulated b y the calcium-activated phosphatase calcineurin, which can be co-transporte d with NFAT to the nucleus to maintain it transcriptionally active for the duration of calcium signaling. When the calcium signal ceases, NFAT is expo rted to the cytoplasm, and different NFAT kinases have been reported to opp ose calcineurin activities and regulate the nuclear export of NFAT, Here we show that p38 MAPK phosphorylates in vitro and interacts in vivo with NFAT p, Furthermore, the activation of this pathway in HeLa cells by cotransfect ion with activated MKK6 and p38 counteracts the calcium-induced nuclear acc umulation of NFATp but not that of NFATc, By contrast, activation of JNK or ERR pathways failed to modify the nuclear shuttling of NFATp. Consistently , activation of p38, but not the JNK MAPK pathway, results in the inhibitio n of NFAT p-driven transcription. In addition, the inhibition of the nuclea r accumulation of NFATp by p38 appears to be mediated through the activatio n of NFATp nuclear export and takes place in a Leptomycin B-sensitive fashi on, suggesting the involvement of the exportin CRM1 in this process. Thus, the p38 signal transduction pathway appears to play an important role in th e regulation of the nuclear shuttling of NFATp and in cellular homeostasis.