Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway
Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway
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DOI：
10.1074/jbc.272.13.8288
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发表时间：
1997-03-28
影响因子：
4.8
通讯作者：
Johnson, GL
中科院分区：
文献类型：
--
作者：
Gerwins, P;Blank, JL;Johnson, GL
丝裂原活化蛋白激酶（MAPK）是响应于多种细胞外信号而活化的连续激酶级联的组分。MAPK家族的成员包括细胞外应答激酶（ERK或p42/44（MAPK））、c-Jun氨基末端激酶（JNK）和p38/Hog 1蛋白激酶。MAPK被MAPK激酶（MKK或MEK）磷酸化和激活，MAPK激酶又被MKK/MEK激酶（Raf和MKKK/MEKK）磷酸化和激活。我们已经分离出两个cDNA编码一种新的MEK激酶，MEKK 4的剪接变体。MEKK 4 mRNA在小鼠组织中广泛表达，编码约180 kDa的蛋白质。MEKK 4羧基末端催化结构域与MEKK 1、2和3的催化结构域约55%同源。MEKK 4的氨基末端区域与先前克隆的MEKK蛋白几乎没有序列同源性。MEKK 4特异性激活JNK途径，但不激活ERK或p38，将其与能够激活ERK途径的MEKK 1、2和3区分开来。MEKK 4定位于核周囊泡区室中，类似于凝胶。MEKK 4与Cdc 42和Rac结合; MEKK 4的激酶失活突变体阻断Cdc 42/Rac对JNK通路的刺激。MEKK 4具有推定的pleckstrin同源结构域和富含脯氨酸的基序，表明其特定的调节功能与之前表征的MEKK不同。
Mitogen-activated protein kinases (MAPKs) are components of sequential kinase cascades that are activated in response to a variety of extracellular signals, Members of the MAPK family include the extracellular response kinases (ERKs or p42/44(MAPK)), the c-Jun aminoterminal kinases (JNKs), and the p38/Hog 1 protein kinases. MAPKs are phosphorylated and activated by MAPK kinases (MKKs or MEKs), which in turn are phosphorylated and activated by MKK/MEK kinases (Raf and MKKK/MEKKs). We have isolated two cDNAs encoding splice variants of a novel MEK kinase, MEKK4. The MEKK4 mRNA is widely expressed in mouse tissues and encodes for a protein of approximately 180 kDa. The MEKK4 carboxyl-terminal catalytic domain is approximately 55% homologous to the catalytic domains of MEKKs 1, 2, and 3. The amino-terminal region of MEKK4 has little sequence homology to the previously cloned MEKK proteins. MEKK4 specifically activates the JNK pathway but not ERKs or p38, distinguishing it from MEKKs 1, 2 and 3, which are capable of activating the ERK pathway. MEKK4 is localized in a perinuclear, vesicular compartment similar to the Gels. MEKK4 binds to Cdc42 and Rac; kinase-inactive mutants of MEKK4 block Cdc42/Rac stimulation of the JNK pathway. MEKK4 has a putative pleckstrin homology domain and a proline-rich motif, suggesting specific regulatory functions different from those of the previously characterized MEKKs.