Tumor necrosis factor alpha rapidly activates the mitogen-activated protein kinase (MAPK) cascade in a MAPK kinase kinase-dependent, c-Raf-1-independent fashion in mouse macrophages.
Tumor necrosis factor alpha rapidly activates the mitogen-activated protein kinase (MAPK) cascade in a MAPK kinase kinase-dependent, c-Raf-1-independent fashion in mouse macrophages.
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肿瘤坏死因子 α 在小鼠巨噬细胞中以 MAPK 激酶激酶依赖性、不依赖于 c-Raf-1 的方式快速激活丝裂原激活蛋白激酶 (MAPK) 级联。
DOI：
10.1073/pnas.92.5.1614
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发表时间：
1995
影响因子：
11.1
通讯作者：
Riches,DW
中科院分区：
文献类型：
--
作者：
Winston,BW;Lange-Carter,CA;Gardner,AM;Johnson,GL;Riches,DW
肿瘤坏死因子α (TNF α)与两种细胞表面受体CD120a （p55）和CD120b （p75）结合，这两种受体属于TNF/神经生长因子受体家族，其信号通过在质膜平面上的受体聚合而启动。受体交联激活的初始信号事件尚不清楚，尽管配体与CD120a结合后不久就会激活丝裂原活化蛋白激酶（MAPK）级联。在本研究中，我们研究了小鼠巨噬细胞CD120a交联后介导42-kDa MAPK p42mapk/erk2活化的上游激酶。小鼠巨噬细胞暴露于TNF α刺激MAPK/ERK激酶（MEK）活性的时间依赖性增加，该活性暂时先于p42mapk/erk2的峰值激活。MEKs是双特异性苏氨酸/酪氨酸激酶，作为Ras/Raf、MEK激酶（MEKK）和Mos等多种信号通路的汇聚点。发现巨噬细胞与TNF α孵育可短暂刺激MEKK，其活性在暴露后30秒内达到峰值，并在5分钟内逐渐降至基础水平。相比之下，在这些条件下，没有检测到c-Raf-1或Raf-B的激活。这些数据表明，响应TNF α的MAPK级联的激活是由MEKK和MEK以不依赖于c-Raf-1和raf - b的方式顺序激活介导的。
Tumor necrosis factor alpha (TNF alpha) is bound by two cell surface receptors, CD120a (p55) and CD120b (p75), that belong to the TNF/nerve growth factor receptor family and whose signaling is initiated by receptor multimerization in the plane of the plasma membrane. The initial signaling events activated by receptor crosslinking are unknown, although activation of the mitogen-activated protein kinase (MAPK) cascade occurs shortly after ligand binding to CD120a. In this study, we investigated the upstream kinases that mediate the activation of the 42-kDa MAPK p42mapk/erk2 following crosslinking of CD120a in mouse macrophages. Exposure of mouse macrophages to TNF alpha stimulated a time-dependent increase in the activity of MAPK/ERK kinase (MEK) that temporally preceded peak activation of p42mapk/erk2. MEKs, dual-specificity threonine/tyrosine kinases, act as a convergence point for several signaling pathways including Ras/Raf, MEK kinase (MEKK), and Mos. Incubation of macrophages with TNF alpha was found to transiently stimulate a MEKK that peaked in activity within 30 sec of exposure and progressively declined toward basal levels by 5 min. By contrast, under these conditions, activation of either c-Raf-1 or Raf-B was not detected. These data suggest that the activation of the MAPK cascade in response to TNF alpha is mediated by the sequential activation of a MEKK and a MEK in a c-Raf-1- and Raf-B-independent fashion.