Integrin (alpha 6 beta 4) regulation of eIF-4E activity and VEGF translation: a survival mechanism for carcinoma cells

J Cell Biol. 2002 Jul 8;158(1):165-74. doi: 10.1083/jcb.200112015. Epub 2002 Jul 8.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antigens, Surface / metabolism*
  • Apoptosis
  • Breast Neoplasms / metabolism
  • Cell Survival
  • Cytoplasm / metabolism
  • Endothelial Growth Factors / metabolism*
  • Eukaryotic Initiation Factor-4E
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Integrin alpha6beta4
  • Integrins / metabolism*
  • Lymphokines / metabolism*
  • Oligonucleotides, Antisense / pharmacology
  • Peptide Initiation Factors / metabolism*
  • Phosphorylation
  • Polyribosomes / metabolism
  • Protein Structure, Tertiary
  • Protein Transport
  • RNA, Bacterial / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Antigens, Surface
  • Endothelial Growth Factors
  • Eukaryotic Initiation Factor-4E
  • Integrin alpha6beta4
  • Integrins
  • Lymphokines
  • Oligonucleotides, Antisense
  • Peptide Initiation Factors
  • RNA I
  • RNA, Bacterial
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors