Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells.
We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the alpha 6 beta 4 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 (eIF-4E). The regulation of 4E-BP1 phosphorylation by alpha 6 beta 4 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 alpha 6 beta 4-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 alpha 6 beta 4 in carcinoma progression.
Chung
Jun
J
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Bachelder
Robin E
RE
Lipscomb
Elizabeth A
EA
Shaw
Leslie M
LM
Mercurio
Arthur M
AM
D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism*; D039561:Eukaryotic Initiation Factor-4E; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000378:metabolism*; D008222:Lymphokines / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D012329:RNA, Bacterial / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000954:Antigens, Surface; D016228:Endothelial Growth Factors; D039561:Eukaryotic Initiation Factor-4E; D039161:Integrin alpha6beta4; D016023:Integrins; D008222:Lymphokines; D016376:Oligonucleotides, Antisense; D010448:Peptide Initiation Factors; C042027:RNA I; D012329:RNA, Bacterial; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors