Role of MEKK2-MEK5 in the regulation of TNF-α gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells
Role of MEKK2-MEK5 in the regulation of TNF-α gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells
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DOI：
10.1073/pnas.081021898
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发表时间：
2001-04-10
影响因子：
11.1
通讯作者：
Gelfand, EW
中科院分区：
文献类型：
--
作者：
Chayama, K;Papst, PJ;Gelfand, EW
肥大细胞上的高亲和力IgE受体（Fc ε RI）与IgE和多价抗原的交联触发丝裂原活化蛋白（MAP）激酶活化和细胞因子基因表达。我们在这里报告，MAP激酶激酶4（MKK 4）基因中断不影响MAP激酶激活或细胞因子基因表达的Fc γ RI在胚胎干细胞衍生的肥大细胞的交联反应。MKK 7响应于Fc β RI的交联而被激活，并且这种激活被MAP/ERK激酶（MEK）激酶2（MEKK 2）基因破坏抑制。此外，小鼠肥大细胞系MC/9中激酶失活的MKK 7的表达抑制了响应于Fe epsilon RI交联的c-Jun NH 2末端激酶（JNK）激活，而激酶失活的MKK 4的表达不影响该刺激引起的JNK激活。然而，Fc干扰素诱导的肿瘤坏死因子-α（TNF-α）基因启动子的激活不受激酶失活MKK 7表达的影响。我们描述了一种替代途径，MEKK 2通过该途径激活MEK 5和大MAP激酶1/细胞外信号调节激酶5以及MKK 7和JNK，并且该途径的中断抑制TNF-α启动子的激活。这些发现表明，通过抗原交联的INK活化依赖于MEKK 2-MKK 7途径，并且肥大细胞中的细胞因子产生部分地由信号传导复合物MEKK 2-MEK 5-ERK 5调节。
Cross-linking of the high-affinity IgE receptor (Fc epsilon RI) on mast cells with IgE and multivalent antigen triggers mitogen-activated protein (MAP) kinase activation and cytokine gene expression. We report here that MAP kinase kinase 4 (MKK4) gene disruption does not affect either MAP kinase activation or cytokine gene expression in response to cross-linking of Fc epsilon RI in embryonic stem cell-derived mast cells. MKK7 is activated in response to crosslinking of Fc epsilon RI, and this activation is inhibited by MAP/ERK kinase (MEK) kinase 2 (MEKK2) gene disruption. In addition, expression of kinase-inactive MKK7 in the murine mast cell line MC/9 inhibits c-Jun NH2-terminal kinase (JNK) activation in response to cross-linking of Fc epsilon RI, whereas expression of kinase-inactive MKK4 does not affect JNK activation by this stimulus. However, Fc epsilon RI-induced activation of the tumor necrosis factor-alpha (TNF-alpha) gene promoter is not affected by expression of kinase-inactive MKK7. We describe an alternative pathway by which MEKK2 activates MEK5 and big MAP kinase1/extracellular signal-regulated kinase 5 in addition to MKK7 and JNK, and interruption of this pathway inhibits TNF-alpha promoter activation. These findings suggest that INK activation by antigen cross-linking is dependent on the MEKK2-MKK7 pathway, and cytokine production in mast cells is regulated in part by the signaling complex MEKK2-MEK5-ERK5.