The p38 pathway provides negative feedback for Ras proliferative signaling
The p38 pathway provides negative feedback for Ras proliferative signaling
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DOI：
10.1074/jbc.m002856200
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发表时间：
2000-12-15
影响因子：
4.8
通讯作者：
Stacey, DW
中科院分区：
文献类型：
--
作者：
Chen, G;Hitomi, M;Stacey, DW
Ras可激活三种丝裂原活化蛋白激酶（mapk），包括ERK、JNK和p38。尽管ERK和JNK在Ras信号传导中的重要作用已经确立，但p38的作用仍不清楚。在这里，我们证明p38通路通过反馈机制作为Pas增殖信号的负调节因子。致癌Ras激活p38和两种p38活化蛋白激酶，mapk活化蛋白激酶2 （MK2）和p58相关/活化蛋白激酶（PRAK）。MK2和PRAK反过来抑制pas诱导的基因表达和细胞增殖，而两种突变的PRAKs对has没有反应，几乎没有影响。此外，组成型p38激活剂MKK6也以p38依赖的方式抑制Pas活性，而p38的强效化学诱导剂亚砷酸盐仅在需要Pas活性的肿瘤细胞系中抑制增殖。Ras刺激p38通路需要MEK。p38通路通过阻断JNK的激活来抑制Pas活性，而不影响ERK，这一点可以通过JNKK2或JNK1的共表达逆转prak介导的Pas诱导的细胞增殖抑制来证明。因此，这些研究建立了一个负反馈机制，通过MAPK通路的信号整合来调节Pas的增殖活性。
Ras activates three mitogen-activated protein kinases (MAPKs) including ERK, JNK and p38. Whereas the essential roles of ERK and JNK in Ras signaling has been established, the contribution of p38 remains unclear. Here we demonstrate that the p38 pathway functions as a negative regulator of Pas proliferative signaling via a feedback mechanism. Oncogenic Ras activated p38 and two p38-activated protein kinases, MAPK-activated protein kinase 2 (MK2) and p58-related/activated protein kinase (PRAK). MK2 and PRAK in turn suppressed Pas-induced gene expression and cell proliferation, whereas two mutant PRAKs, unresponsive to has, had little effect. Moreover, the constitutive p38 activator MKK6 also suppressed Pas activity in a p38-dependent manner whereas arsenite, a potent chemical inducer of p38, inhibited proliferation only in a tumor cell line that required Pas activity. MEK was required for Ras stimulation of the p38 pathway. The p38 pathway inhibited Pas activity by blocking activation of JNK, without effect upon ERK, as evidenced by the fact that PRAK-mediated suppression of Pas-induced cell proliferation was reversed by coexpression of JNKK2 or JNK1. These studies thus establish a negative feedback mechanism by which Pas proliferative activity is regulated via signaling integrations of MAPK pathways.