Regulation of Breast Carcinoma Chemotaxis by the Integrin Alpha6Beta4
Abstract
Breast carcinoma invasion is a complex process in which the normal balance of cellular adhesion, proteolysis and directed migration is altered leading to penetration of the basement membrane and underlying stroma. Work from our lab has shown that expression of the integrin Alpha6Beta4 in breast carcinoma cells enhances their invasiveness. With funding from this grant, I have shown that integrin Alpha6Beta4 expression in breast carcinoma cells leads to an increase in chemotactic (directed) migration toward lysophosphatidic acid (LPA) and is required for the lamellae formation. Both lamellae formation and chemotactic migration are inhibited or gated' by cAMP. My results reveal that a critical function of Alpha6Beta4 is to suppress the intracellular cAMP concentration by increasing the activity of a rolipram-sensitive, cAMP-specific phosphodiesterase (PDE). Also, my results show that the small GTPase RhoA controls lamellipodial formation, is required for directed migration and is preferentially activated by the Alpha6Beta4 integrin. Furthermore, the ability of Alpha6Beta4 to influence cAMP metabolism is critical to Rho activation and function. I also have found that cAMP metabolism and the Alpha6Beta4 integrin can control the activation of Raci, a protein that can counteract the functions of RhoA. The goal of this study is to understand how integrin Alpha6Beta4 enhances tamellipodial formation and chemotaxis in breast carcinoma cells by identifying the signaling pathways involved in these processes. Toward this goal, I have made considerable progress and have created a firm basis for future work as an independent investigator.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2001
- Accession Number
- ADA398207
Entities
People
- Arthur M Mercurio
- Kathleen L. O'connor
Organizations
- Beth Israel Deaconess Medical Center