Mnk mediates integrin α6β4-dependent eIF4E phosphorylation and translation of VEGF mRNA.
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.
Department of Emergency Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. nkorne@lsuhsc.edu
Nadejda L
NL
Korneeva
Young Hwa
YH
Soung
Hong Im
HI
Kim
Anthony
A
Giordano
Robert E
RE
Rhoads
Hermann
H
Gram
Jun
J
Chung
D000814:Aniline Compounds / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free; D015536:Down-Regulation; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039161:Integrin alpha6beta4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000814:Aniline Compounds; D002070:Butadienes; C466997:CGP 57380; D016895:Culture Media, Serum-Free; D039561:Eukaryotic Initiation Factor-4E; D039161:Integrin alpha6beta4; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D011687:Purines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C113580:U 0126; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C491395:MKNK1 protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases