Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Mol Cell Biol. 2012 Jan;32(1):88-95. doi: 10.1128/MCB.05770-11. Epub 2011 Oct 24.
The extracellular signal-regulated kinase (ERK) pathway participates in the control of numerous cellular processes, including cell proliferation. Since its activation kinetics are critical for to its biological effects, they are tightly regulated. We report that the protein translation factor, eukaryotic translation initiation factor 3, subunit a (eIF3a), binds to SHC and Raf-1, two components of the ERK pathway. The interaction of eIF3a with Raf-1 is increased by β-arrestin2 expression and transiently decreased by epidermal growth factor (EGF) stimulation in a concentration-dependent manner. The EGF-induced decrease in Raf-1-eIF3a association kinetically correlates with the time course of ERK activation. eIF3a interferes with Raf-1 activation and eIF3a downregulation by small interfering RNA enhances ERK activation, early gene expression, DNA synthesis, expression of neuronal differentiation markers in PC12 cells, and Ras-induced focus formation in NIH 3T3 cells. Thus, eIF3a is a negative modulator of ERK pathway activation and its biological effects.
细胞外信号调节激酶（ERK）通路参与控制众多细胞过程，包括细胞增殖。由于其激活动力学对于其生物学效应至关重要，因此它们受到严格的调节。我们报告称，蛋白质翻译因子，真核翻译起始因子 3 亚基 a（eIF3a），与 ERK 通路的两个组成部分 SHC 和 Raf-1 结合。β-arrestin2 表达增加和表皮生长因子（EGF）刺激以浓度依赖的方式瞬时降低 Raf-1-eIF3a 相互作用。EGF 诱导的 Raf-1-eIF3a 缔合减少与 ERK 激活的时间过程呈动力学相关。eIF3a 干扰 Raf-1 激活，通过小干扰 RNA 下调 eIF3a 可增强 ERK 激活、早期基因表达、DNA 合成、PC12 细胞中神经元分化标志物的表达以及 NIH 3T3 细胞中 Ras 诱导的焦点形成。因此，eIF3a 是 ERK 通路激活及其生物学效应的负调节剂。
