Integrin Regulation of Akt and Breast Cancer Metastasis
Abstract
We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the alpha6beta4 integrin enhances 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-BPl), a translational repressor that inhibits the function of translation initiation factor 4E (eIF-4E) The regulation of 4E-BPl phosphorylation by alpha6beta4 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-BPl. Importantly, we show that this alpha6beta4-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 P13-K 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 alpha6beta4 in carcinoma progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2002
- Accession Number
- ADA407289
Entities
People
- Arthur M Mercurio
- Jun Chung
Organizations
- Beth Israel Deaconess Medical Center