Wei Xudong, Sun Weiyong, Fan Ruihua, Hahn Joanne, Joetham Anthony, Li Guiming, Webb Saiphone, Garrington Timothy, Dakhama Azzeddine, Lucas Joseph, Johnson Gary L, Gelfand Erwin W
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Co 80206, USA.
Eur J Immunol. 2003 Oct;33(10):2903-9. doi: 10.1002/eji.200324127.
Mitogen-activated protein kinase (MAPK) cascades play essential roles in the transduction of extracellular signals to cytoplasmic and nuclear effectors. The MAPK kinase kinase MEKK2 is essential for activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5). These pathways are important for expression of specific cytokine genes in mast cells following cross-linking of the high-affinity IgE receptor (FcepsilonRI). A consequence of ERK5 activation is activation of the transcriptional factor myocyte enhancing factor-2C (MEF2C), leading to increased c-Jun expression. We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5. Following phosphorylation of MEF2C, activated MEF2C regulates transcription of c-Jun but not TNF-alpha. Inhibition of ERK5, MEK5 activation or activation of MEKK2-deficient mast cells was associated with inhibition of MEF2C phosphorylation and a decrease in c-Jun expression. Thus, these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells following FcepsilonRI cross-linking. These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcepsilonRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.
丝裂原活化蛋白激酶（MAPK）级联反应在将细胞外信号转导至细胞质和细胞核效应器的过程中发挥着重要作用。MAPK激酶激酶MEKK2对于激活c-Jun氨基末端激酶（JNK）和细胞外信号调节激酶5（ERK5）至关重要。在高亲和力IgE受体（FcepsilonRI）交联后，这些信号通路对于肥大细胞中特定细胞因子基因的表达很重要。ERK5激活的一个结果是转录因子肌细胞增强因子2C（MEF2C）的激活，导致c-Jun表达增加。我们研究了MEF2C激活在肥大细胞中的作用，并证明其需要MEKK2-MEK5-ERK5信号级联反应的顺序激活。MEF2C磷酸化后，活化的MEF2C调节c-Jun的转录，但不调节肿瘤坏死因子-α（TNF-α）的转录。抑制ERK5、MEK5激活或MEKK2缺陷型肥大细胞的激活与MEF2C磷酸化的抑制以及c-Jun表达的降低有关。因此，这些数据定义了一个在FcepsilonRI交联后肥大细胞中c-Jun转录激活中的激活模块，即MEKK2-MEK5-ERK5-MEF2C。这些结果证明了MEF2C在通过FcepsilonRI激活的肥大细胞中诱导c-Jun表达中具有新的重要的、依赖MEKK2的作用，这是一条不同于MEKK2-MEK5-ERK5在调节肥大细胞细胞因子产生中所涉及的途径。
