Department of Cancer Biology
Antigens, Surface; Apoptosis; Breast Neoplasms; Cell Survival; Cytoplasm; Endothelial Growth Factors; Eukaryotic Initiation Factor-4E; *Gene Expression Regulation, Neoplastic; Humans; Integrin alpha6beta4; Integrins; Lymphokines; Oligonucleotides, Antisense; Peptide Initiation Factors; Phosphorylation; Polyribosomes; Protein Structure, Tertiary; Protein Transport; RNA, Bacterial; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
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.
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Citation: J Cell Biol. 2002 Jul 8;158(1):165-74. Epub 2002 Jul 8. Link to article on publisher's site
Chung, Jun; Bachelder, Robin E.; Lipscomb, Elizabeth A.; Shaw, Leslie M.; and Mercurio, Arthur M., "Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells" (2002). Cancer Biology Publications and Presentations. 196.