Menges C W, McCance D J
Department of Biochemistry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Oncogene. 2008 May 1;27(20):2934-40. doi: 10.1038/sj.onc.1210957. Epub 2007 Dec 3.
The Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)-AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf-MAPK and PI3K-AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K-AKT pathway can inhibit the Raf-MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf-MAPK pathway to negatively regulate the PI3K-AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf-MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA2. EphA2-mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras-PI3K-AKT pathway as a necessary event for the Raf-MEK1-regulated cellular arrest.
Raf-丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶（PI3K）-AKT信号通路是小GTP酶Ras的两个下游效应器。尽管这两条信号通路均受Ras正向调控，但Raf-MAPK和PI3K-AKT信号通路已被证明在细胞内控制着相反的功能，这表明需要进行相互调控。在诸如肌肉分化等过程中，PI3K-AKT信号通路可直接抑制Raf-MAPK信号通路。在此，我们描述了在细胞停滞期间Raf-MAPK信号通路对PI3K-AKT信号通路进行负向调控的能力。Raf或甲基乙二酮1（MEK1）的组成型激活会导致AKT的抑制和细胞停滞。此外，我们表明Raf-MEK1信号的激活会通过 Ephrin 受体EphA2对Ras产生负反馈抑制。EphA2介导的负反馈抑制是Raf诱导的AKT抑制和细胞周期停滞所必需的，因此证实了Ras-PI3K-AKT信号通路的抑制是Raf-MEK1调控的细胞停滞的必要事件
