Dawson Christopher W, Laverick Louise, Morris Mhairi A, Tramoutanis Giorgos, Young Lawrence S
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
J Virol. 2008 Apr;82(7):3654-64. doi: 10.1128/JVI.01888-07. Epub 2008 Jan 16.
The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is an oncogenic protein which has previously been shown to engage the NF-kappaB, stress-activated MAP kinase, phosphatidylinositol 3-kinase (PI 3-kinase), and extracellular-regulated kinase (ERK)-MAPK pathways. In this study, we demonstrate that LMP1 activates ERK-MAPK in epithelial cells via the canonical Raf-MEK-ERK-MAPK pathway but in a Ras-independent manner. In agreement with the results of a previous study (B. A. Mainou, D. N. Everly, Jr., and N. Raab-Traub, J. Virol. 81:9680-9692, 2007), we show that the ability of LMP1 to activate ERK-MAPK mapped to its CTAR1 domain, the TRAF binding domain previously implicated in PI 3-kinase activation. A role for ERK-MAPK in LMP1-induced epithelial cell motility was identified, as LMP1-expressing cells displayed increased rates of haptotactic migration compared to those of LMP1-negative cells. These data implicate the ERK-MAPK pathway in LMP1-induced effects associated with transformation, suggesting that this pathway may contribute to the oncogenicity of LMP1 through its ability to promote cell motility and to enhance the invasive properties of epithelial cells.
爱泼斯坦-巴尔病毒（EBV）潜伏膜蛋白1（LMP1）是一种致癌蛋白，此前已证明它可激活核因子-κB、应激激活的丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇3激酶（PI 3激酶）和细胞外调节激酶（ERK）-MAPK信号通路。在本研究中，我们证明LMP1通过经典的Raf-MEK-ERK-MAPK信号通路在不依赖Ras的情况下激活上皮细胞中的ERK-MAPK。与先前一项研究（B. A. Mainou、D. N. Everly, Jr.和N. Raab-Traub，《病毒学杂志》81:9680-9692，2007年）的结果一致，我们发现LMP1激活ERK-MAPK的能力定位于其CTAR1结构域，即先前与PI 3激酶激活有关的TRAF结合结构域。我们确定了ERK-MAPK在LMP1诱导的上皮细胞运动中的作用，因为与LMP1阴性细胞相比，表达LMP1的细胞显示出趋触性迁移速率增加。这些数据表明ERK-MAPK信号通路参与了LMP1诱导的与细胞转化相关的效应，提示该信号通路可能通过促进细胞运动和增强上皮细胞侵袭特性的能力而有助于LMP1的致癌性。
