Regulation of Cell Survival in Human Breast Cancer Cells by Sphingosine Kinase
Abstract
EDG-1 is a GPCR for sphingosine-1-phosphate (SPP) that mediates SPP-directed cell migration and vascular maturation. Cell migration toward PDGF, which stimulates sphingosine kinase and increases SPP levels, was dependent on expression of EDG-1, and conversely, deletion of EDG-1, inhibition of sphingosine kinase or treatment with pertussis toxin to uncouple Gi-linked receptors suppressed chemotaxis toward PDGF. PDGF activated EDG-1 in a sphingosine kinase-dependent manner as shown by translocation of B-arrestin. PDGF induced tyrosine phosphorylation of focal adhesion proteins, including FAK and Src, activation of the small GTPase Rae, essential for the protrusion of lamellipodia and forward movement, and p38 were nearly eliminated by the deletion of EDG-1, whereas tyrosine phosphorylation of the PDGFR and ERK activation were unaltered. Our results establish a new paradigm for receptor cross-communication in which transactivation of a GPCR, EDG-1, by a receptor tyrosine kinase, the PDGFR, is critical for cell motility.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2001
- Accession Number
- ADA390002
Entities
People
- John P. Hobson
Organizations
- Georgetown University