Dimerization through the catalytic domain is essential for MEKK2 activation
Dimerization through the catalytic domain is essential for MEKK2 activation
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DOI：
10.1074/jbc.m414258200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Su, B
中科院分区：
文献类型：
--
作者：
Cheng, JK;Yu, L;Su, B
丝裂原活化蛋白激酶(MAPK)级联是真核细胞用来响应广泛的细胞外刺激的细胞内信号网络的中心组成部分。MAPK通过由MAPK、MAPK和MKK(MAP3K)组成的模块激活。由于其在MAPK模块中的独特位置，MAP3K在通过MAPK级联传递上游受体介导的信号以诱导生理反应方面起着至关重要的作用。然而，MAP3K调控和激活的潜在分子机制在很大程度上仍不清楚。在这项研究中，我们证明了MAP3K MEKK2的激活需要二聚化。我们将MEKK2二聚基序映射到其催化区域，表明NH2-末端区域不是MEKK2二聚体形成所必需的。我们还发现，非活性的、非磷酸化的MEKK2比磷酸化的MEKK2形成的二聚体要多得多，因此，活性的MEKK2。此外，阻止MEKK2二聚体的形成可抑制MEKK2介导的JNK激活。利用化学诱导的二聚体系统，我们进一步证明了体内MEKK2二聚体的形成增强了MEKK2依赖的JNK的激活和JNK/AP-1报告基因的转录。综上所述，这些结果提示了MEKK2调节和激活的新机制。
Mitogen-activated protein kinase (MAPK) cascades are the central components of the intracellular signaling networks that eukaryotic cells use to respond to a wide spectrum of extracellular stimuli. MAPKs are activated through a module consisting of a MAPK, a MAPK kinase (MKK), and a MKK kinase (MAP3K). Because of its unique position in the MAPK module, a MAP3K is crucial in relaying the upstream receptor-mediated signals through the MAPK cascades to induce physiological responses. Yet, the underlying molecular mechanism of MAP3K regulation and activation remains largely unknown. In this study, we demonstrated that MAP3K MEKK2 activation requires dimerization. We mapped the MEKK2 dimerization motif in its catalytic domain and showed that the NH2-terminal region is not required for MEKK2 dimer formation. We also found that the inactive, non-phosphorylated MEKK2 formed significantly more dimers than the phosphorylated and, hence, active MEKK2. Moreover, prevention of MEKK2 dimer formation inhibited MEKK2-mediated JNK activation. Using a chemical-induced dimerization system, we further demonstrated that MEKK2 dimer formation in vivo augmented MEKK2-dependent JNK activation and JNK/AP-1 reporter gene transcription. Together, these results suggest a novel mechanism underlying MEKK2 regulation and activation.