Mnk Mediates Integrin α6β4-Dependent eIF4E Phosphorylation and Translation of VEGF mRNA

It was previously shown that integrin alpha 6 beta 4 contributes to translation of cancer-related mRNAs such as VEGF via initiation factor eIF4E. In this study, we found that integrin alpha 6 beta 4 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 alpha 6 beta 4 and mediates the alpha 6 beta 4 signaling, important for translational control. Integrin alpha 6 beta 4 signals through MEK and p38 MAPK to increase phosphorylation of Mnk1 and eIF4E. Inhibition of Mnk1 activity by CGP57380 or downregulation by shRNA blocks alpha 6 beta 4-dependent translation of VEGF mRNA. Our studies suggest that Mnk1 could be a therapeutic target in cancers where the integrin alpha 6 beta 4 level is high. Mol Cancer Res; 8(12); 1571-8. (C) 2010 AACR.