Kesavan Kamala, Lobel-Rice Katherine, Sun Weiyong, Lapadat Razvan, Webb Saiphone, Johnson Gary L, Garrington Timothy P
Department of Pharmacology and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
J Cell Physiol. 2004 Apr;199(1):140-8. doi: 10.1002/jcp.10457.
Mitogen-activated protein kinases (MAPKs) are regulated by MAPK kinases (MKKs), which are in turn regulated by MKK kinases (MKKKs). While a single MKKK can regulate several different MAPK family members, and several MKKKs can often activate the same MAPK, emerging evidence indicates a unique role for individual MKKKs in acting as signaling nodes to coordinately activate different subsets of MAPKs in response to specific cellular stimuli. Thus, while there is much apparent overlap in MAPK regulation by different MKKKs, each MKKK serves a specific purpose in regulation of unique cellular functions. The purpose of this study was to define the specific role of MEKK2, an MKKK, in MAPK regulation and cell function. MEKK2 coordinately activates the ERK5 and JNK pathways. Targeted disruption of MEKK2 expression causes loss of ERK5 and JNK activation in response to FGF-2 in mouse embryonic fibroblasts (MEFs). FGF-2 receptor signaling requires MEKK2 for induction of mRNA for c-Jun, Fra-1, and Fra-2, components of the AP-1 transcription complex. In FGF-2-stimulated MEKK2-/- fibroblasts, c-Jun phosphorylation is inhibited, consistent with a loss of JNK activation. Thus, MEKK2 regulates AP-1 activity at two levels, by regulating both expression of AP-1 components and c-Jun N-terminal phosphorylation. One function of the AP-1 transcription complex is to regulate cytokine gene expression. Expression of IL-1alpha, IL-1beta, IL-6, and TNFalpha is inhibited in MEKK2-/- fibroblasts. Bacterial lipopolysaccharide (LPS) and TNFalpha neither activate ERK5 nor require MEKK2 for JNK activation, demonstrating specificity of MEKK2 in FGF-2 receptor signaling and control of cytokine gene expression.
丝裂原活化蛋白激酶（MAPKs）由MAPK激酶（MKKs）调节，而MKKs又由MKK激酶（MKKKs）调节。虽然单个MKKK可以调节几种不同的MAPK家族成员，并且几种MKKKs通常可以激活同一种MAPK，但新出现的证据表明，单个MKKKs在作为信号节点以响应特定细胞刺激而协调激活不同的MAPK亚群方面具有独特作用。因此，虽然不同的MKKKs在MAPK调节方面存在明显的重叠，但每个MKKK在调节独特的细胞功能中都有特定作用。本研究的目的是确定MKKK之一的MEKK2在MAPK调节和细胞功能中的具体作用。MEKK2可协调激活ERK5和JNK途径。靶向破坏MEKK2的表达会导致小鼠胚胎成纤维细胞（MEFs）中ERK5和JNK激活在响应FGF-2时丧失。FGF-2受体信号传导需要MEKK2来诱导AP-1转录复合物的组成成分c-Jun、Fra-1和Fra-2的mRNA。在FGF-2刺激的MEKK2基因敲除成纤维细胞中，c-Jun磷酸化受到抑制，这与JNK激活丧失一致。因此，MEKK2通过调节AP-1成分的表达和c-Jun N端磷酸化，在两个水平上调节AP-1活性。AP-1转录复合物的一个功能是调节细胞因子基因表达。MEKK2基因敲除成纤维细胞中IL-1α、IL-1β、IL-6和TNFα的表达受到抑制。细菌脂多糖（LPS）和TNFα既不激活ERK5，JNK激活也不需要MEKK2，这证明了MEKK2在FGF-2受体信号传导和细胞因子基因表达控制中的特异性。
