Cross-talk between JNK/SAPK and ERK/MAPK pathways
Cross-talk between JNK/SAPK and ERK/MAPK pathways
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DOI：
10.1074/jbc.m303264200
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发表时间：
2003-07-18
影响因子：
4.8
通讯作者：
Tzivion, G
中科院分区：
文献类型：
--
作者：
Shen, YH;Godlewski, J;Tzivion, G
混合谱系激酶（mlk）是一个丝氨酸/苏氨酸激酶家族，在SAPK信号级联中起作用。在体内，MLKs通过直接磷酸化和激活JNK激酶SEK-1 （MKK4和-7）来激活JNK/SAPK。重要的是，MLK成员MLK3/SPRK最近被证明是神经酰胺和肿瘤坏死因子- α (tnf - α)的直接靶点，并介导Jurkat细胞中tnf - α和神经酰胺诱导的JNK活化。本文报道了MLK3在体外可以直接磷酸化并激活MEK-1，在COS-7细胞中也可以诱导MEK在其激活位点磷酸化。令人惊讶的是，MEK磷酸化的诱导并不会导致ERK在体内的激活。相反，在表达活性MLK3的细胞中，ERK对生长因子和有丝分裂原的激活产生抗性。这种对ERK激活的限制需要MLK3激酶活性，独立于Raf激活，并且在SEK-1、JNK或jun水平上被JNK通路抑制逆转。这些结果表明，持续的JNK激活以一种需要jun介导的基因转录的方式解除了ERK与MEK的激活。这反过来表明应激激活的JNK通路和丝裂原激活的ERK通路之间存在负串扰关系。因此，我们的研究结果表明，JNK激活剂的一些生物学功能，如tnf - α和神经酰胺，可能归因于它们能够阻断细胞对通过ERK/MAPK途径作用的生长和存活因子的反应。
Mixed lineage kinases (MLKs) are a family of serine/threonine kinases that function in the SAPK signaling cascade. MLKs activate JNK/SAPK in vivo by directly phosphorylating and activating the JNK kinase SEK-1 (MKK4 and -7). Importantly, the MLK member MLK3/SPRK has been shown recently to be a direct target of ceramide and tumor necrosis factor-alpha (TNF-alpha) and to mediate the TNF-alpha and ceramide-induced JNK activation in Jurkat cells. Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells. Surprisingly, this induction of MEK phosphorylation does not result in ERK activation in vivo. Rather, in cells expressing active MLK3, ERK becomes resistant to activation by growth factors and mitogens. This restriction in ERK activation requires MLK3 kinase activity, is independent of Raf activation, and is reversed by JNK pathway inhibition either at the level of SEK-1, JNK, or Jun. These results demonstrate that sustained JNK activation uncouples ERK activation from MEK in a manner requiring Jun-mediated gene transcription. This in turn points to the existence of a negative cross-talk relationship between the stress-activated JNK pathway and the mitogen-activated ERK pathway. Thus, our findings imply that some of the biological functions of JNK activators, such as TNF-alpha and ceramide, may be attributed to their ability to block cell responses to growth and survival factors acting through the ERK/MAPK pathway.