Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism
Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism
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DOI：
10.1073/pnas.141224398
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发表时间：
2001-07-03
影响因子：
11.1
通讯作者：
Fu, H
中科院分区：
文献类型：
--
作者：
Chen, J;Fuji, K;Fu, H
丝氨酸/苏氨酸激酶Raf-1是一种原癌基因产物，是参与正常细胞生长和致癌转化的许多信号通路的中心成分。激活后，Raf-1磷酸化丝裂原活化的蛋白激酶（MEK），进而激活丝裂原活化的蛋白激酶/细胞外信号调节激酶（MAPK/ERKs），导致信号的传播。根据特定的刺激和细胞环境，Raf-1- mek - erk级联调节多种细胞过程，如增殖、分化和凋亡。在这里，我们描述了af-1不依赖于mek - erk的促生存功能。我们发现，在体外和体内，Raf-1与促凋亡的应激激活蛋白激酶ASK1（凋亡信号调节激酶1）相互作用。缺失分析将Raf-1结合位点定位在ASK1的n端调控片段上。这种相互作用允许Raf-1独立于MEK- erk途径抑制细胞凋亡，此外，催化失活形式的Raf-1可以模拟野生型效应，提高了Raf-1不依赖激酶功能的可能性，因此，Raf-1除了具有既定的MEK激酶功能外，还可能通过其蛋白-蛋白相互作用促进细胞存活。
The Ser/Thr kinase Raf-1 is a protooncogene product that is a central component in many signaling pathways involved in normal cell growth and oncogenic transformation, Upon activation, Raf-l phosphorylates mitogen-activated protein kinase kinase (MEK), which in turn activates mitogen-activated protein kinase/extracellular signal-regulated kinases (MAPK/ERKs), leading to the propagation of signals. Depending on specific stimuli and cellular environment, the Raf-1-MEK-ERK cascade regulates diverse cellular processes such as proliferation, differentiation, and apoptosis, Here, we describe a MEK-ERK-independent prosurvival function of Raf-1. We found that Raf-1 interacts with the proapoptotic, stress-activated protein kinase ASK1 (apoptosis signal-regulating kinase 1) in vitro and in vivo. Deletion analysis localized the Raf-1 binding site to the N-terminal regulatory fragment of ASK1. This interaction allows Raf-1 to act independently of the MEK-ERK pathway to inhibit apoptosis, Furthermore, catalytically inactive forms of Raf-1 can mimic the wild-type effect, raising the possibility of a kinase-independent function of Raf-1, Thus, Raf-1 may promote cell survival through its protein-protein interactions in addition to its established MEK kinase function.