TRANSCRIPTIONAL REGULATION BY MAP KINASES
TRANSCRIPTIONAL REGULATION BY MAP KINASES
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DOI：
10.1002/mrd.1080420414
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发表时间：
1995-12-01
影响因子：
2.5
通讯作者：
DAVIS, RJ
中科院分区：
文献类型：
--
作者：
DAVIS, RJ
酪氨酸激酶生长因子受体通过涉及SH 2/3蛋白Grb 2、交换蛋白Sos和Ras的复杂机制激活MAP激酶。GTP结合的Pas蛋白与Raf激酶结合，并启动蛋白激酶级联反应，导致MAP激酶活化。已经描述了三种MAP激酶激酶-c-Raf、c-Mos和Mekk-，它们磷酸化并激活MAP激酶激酶Mek。活化的Mek磷酸化并活化MAP激酶。随后，活化的MAP激酶易位到MAP激酶信号转导途径的许多生理靶点所在的细胞核中。这些底物包括受MAP激酶磷酸化调节的转录因子（例如，Elk-1、c-Myc、c-Jun、c-Fos和C/EBP β）。因此，MAP激酶途径代表了一个重要的机制，信号转导的生长因子受体从细胞表面到细胞核，导致在调节基因expression.Three MAP激酶同源物已被确定在大鼠：Erk 1，Erk 2和Erk 3。与大鼠Erk激酶相似的人MAP激酶也已通过分子克隆鉴定。人Erk 1蛋白激酶已被证明在许多组织中广泛表达为44-kDa蛋白。人Erk 2蛋白激酶是一种41 kDa的蛋白质，广泛表达。相反，已经发现人Erk 3相关蛋白激酶仅在心肌和脑中以高水平表达。这些MAP激酶基因广泛分布于人类基因组中：erk 2位于22q11.2，erk 1位于16p11.2，ek 3位于18 q12 - 21。在酿酒酵母中，已发现5个MAP激酶基因同源物：smk 1，mpk 1，hog 1，fus 3和kss 1。总的来说，这些激酶比已发现的人类erk激酶更加多样化。因此，erks可能只代表一个更大的人类MAP激酶基因家族的一个亚组。该MAP激酶扩展家族的候选者是c-lun NH 2-末端激酶（Jnk），其在激活位点Ser-63和Ser-73处结合并磷酸化转录因子c-lun。这里提出的证据表明，JNK是MAP激酶组的远亲，该激酶组通过Tyr和Thr的双重磷酸化而被激活。(C)1995年Wiley-Liss，Inc.
Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Pas protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described-c-Raf, c-Mos, and Mekk-that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression.Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21.In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smk1, mpk1, hog1, fus3,and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-lun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-lun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr. (C) 1995 Wiley-Liss, Inc.