Department of Emergency Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Mol Cancer Res. 2010 Dec;8(12):1571-8. doi: 10.1158/1541-7786.MCR-10-0091. Epub 2010 Oct 21.
It was previously shown that integrin α6β4 contributes to translation of cancer-related mRNAs such as VEGF via initiation factor eIF4E. In this study, we found that integrin α6β4 regulates the activity of eIF4E through the Ser/Thr kinase Mnk. Although a role for Mnk in various aspects of cancer progression has been established, a link between integrin and Mnk activity has not. Here we show that Mnk1 is a downstream effector of integrin α6β4 and mediates the α6β4 signaling, important for translational control. Integrin α6β4 signals through MEK and p38 MAPK to increase phosphorylation of Mnk1 and eIF4E. Inhibition of Mnk1 activity by CGP57380 or downregulation by shRNA blocks α6β4-dependent translation of VEGF mRNA. Our studies suggest that Mnk1 could be a therapeutic target in cancers where the integrin α6β4 level is high.
先前的研究表明，整合素α6β4 通过起始因子 eIF4E 促进与癌症相关的 mRNA ，如 VEGF 的翻译。在这项研究中，我们发现整合素α6β4 通过丝氨酸/苏氨酸激酶 Mnk 调节 eIF4E 的活性。尽管 Mnk 在癌症进展的各个方面的作用已经得到确立，但整合素与 Mnk 活性之间的联系尚未建立。在这里，我们表明 Mnk1 是整合素α6β4 的下游效应物，并介导对翻译控制很重要的α6β4 信号转导。整合素α6β4 通过 MEK 和 p38 MAPK 信号转导增加 Mnk1 和 eIF4E 的磷酸化。用 CGP57380 抑制 Mnk1 活性或用 shRNA 下调可阻断α6β4 依赖性 VEGF mRNA 的翻译。我们的研究表明，在整合素α6β4 水平较高的癌症中，Mnk1 可能是一种治疗靶点。
