Integrin (α6β4) regulation of eIF-4E activity and VEGF translation:: a survival mechanism for carcinoma cells
Integrin (α6β4) regulation of eIF-4E activity and VEGF translation:: a survival mechanism for carcinoma cells
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DOI：
10.1083/jcb.200112015
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发表时间：
2002-07-08
影响因子：
7.8
通讯作者：
Mercurio, AM
中科院分区：
文献类型：
--
作者：
Chung, J;Bachelder, RE;Mercurio, AM
我们定义了一个新的机制，通过整合素调节生长因子的表达和癌细胞的生存。具体来说，我们证明了alpha6beta4整合素可以增强乳腺癌细胞中血管内皮生长因子（VEGF）的翻译。其机制涉及该整合素刺激4E结合蛋白（4E- bp1）磷酸化和失活的能力，4E结合蛋白是一种抑制真核翻译起始因子4E （elF-4E）功能的翻译抑制因子。alpha6beta4对4E-BP1磷酸化的调控源于该整合素激活PI-3K-Akt通路的能力，因此，雷帕霉素敏感激酶mTOR可以磷酸化4E-BP1。重要的是，我们发现这种依赖于alpha6beta4的VEGF翻译调节通过维持VEGF自分泌信号通路在转移性乳腺癌细胞的存活中发挥重要作用，该信号通路涉及PI-3K和Akt的激活。这些发现表明，整合素介导的PI-3K-Akt的激活被整合素刺激的VEGF表达放大，它们提供了一种机制，证实了alpha6beta4在癌症进展中的作用。
We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the alpha6beta4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells. The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (elF-4E). The regulation of 4E-BP1 phosphorylation by alpha6beta4 derives from the ability of this integrin to activate the PI-3K-Akt pathway and, consequently, the rapamycin-sensitive kinase mTOR that can phosphorylate 4E-BP1. Importantly, we show that this alpha6beta4-dependent regulation of VEGF translation plays an important role in the survival of metastatic breast carcinoma cells by sustaining a VEGF autocrine signaling pathway that involves activation of PI-3K and Akt. These findings reveal that integrin-mediated activation of PI-3K-Akt is amplified by integrin-stimulated VEGF expression and they provide a mechanism that substantiates the reported role of alpha6beta4 in carcinoma progression.