Interaction of MAP kinase with MAP kinase kinase: Its possible role in the control of nucleocytoplasmic transport of MAP kinase
Interaction of MAP kinase with MAP kinase kinase: Its possible role in the control of nucleocytoplasmic transport of MAP kinase
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DOI：
10.1093/emboj/16.8.1901
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发表时间：
1997-04-15
期刊：
影响因子：
11.4
通讯作者：
Nishida, E
中科院分区：
文献类型：
--
作者：
Fukuda, M;Gotoh, Y;Nishida, E
丝裂原活化蛋白激酶（MAPK）级联反应由MAPK及其直接激活剂MAPK激酶（MAPKK）组成，是将各种细胞外刺激物信号传导至细胞核所必需的。在刺激时，MAPK移位至细胞核，而MAPK停留在细胞质中，最近的研究表明，MAPKK的胞浆定位是由其核输出信号（内斯）在近N端区域决定的（残基33-44），然而，决定MAPK的亚细胞分布的机制一直知之甚少，在这里，我们表明，在哺乳动物培养细胞中引入v-Ras、活性STE 11或组成型活性MAPK可以诱导MAPK的核转位，此外，我们发现的证据表明，MAPK通过与MAPK的特异性结合定位于细胞质，MAPK的核积累在MAPK途径激活后，伴随着MAPK和MAPKK之间的复合物的解离，我们已经确定了MAPKK的MAPK结合位点为其N-末端残基1-32。此外，包含MAPK结合位点和MAPKK的内斯序列的肽已被证明足以将MAPK保留在细胞质中。这些发现揭示了MAPK亚细胞分布调控的分子基础，并确定了MAPK作为MAPK细胞质锚定蛋白的新功能。
The mitogen-activated protein kinase (MAPK) cascade consisting of MAPK and its direct activator, MAPK kinase (MAPKK), is essential for signaling of various extracellular stimuli to the nucleus, Upon stimulation, MAPK is translocated to the nucleus, whereas MAPKK stays in the cytoplasm, It has been shown recently that the cytoplasmic localization of MAPKK is determined by its nuclear export signal (NES) in the near N-terminal region (residues 33-44), However, the mechanism determining the subcellular distribution of MAPK has been poorly understood, Here, we show that introduction of v-Ras, active STE11 or constitutively active MAPKK can induce nuclear translocation of MAPK in mammalian cultured cells, Furthermore, we show evidence suggesting that MAPK is localized to the cytoplasm through its specific association with MAPKK and that nuclear accumulation of MAPK is accompanied by dissociation of a complex between MAPK and MAPKK following activation of the MAPK pathway, We have identified the MAPK-binding site of MAPKK as its N-terminal residues 1-32. Moreover, a peptide encompassing the MAPK-binding site and the NES sequence of MAPKK has been shown to be sufficient to retain MAPK to the cytoplasm. These findings reveal the molecular basis regulating subcellular distribution of MAPK, and identify a novel function of MAPKK as a cytoplasmic anchoring protein for MAPK.