EDG‐1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration

Abstract

Sphingosine-1-phosphate (SPP), formed by sphingosine kinase, is the ligand for EDG-1, a GPCR important for cell migration and vascular maturation. Here we show that cytoskeletal rearrangements, lamel- lipodia extensions, and cell motility induced by platelet- derived growth factor (PDGF) are abrogated in EDG-1 null fibroblasts. However, EDG-1 appears to be dis- pensable for mitogenicity and survival effects, even those induced by its ligand SPP and by PDGF. Further- more, PDGF induced focal adhesion formation and activation of FAK, Src, and stress-activated protein kinase 2, p38, were dysregulated in the absence of EDG-1. In contrast, tyrosine phosphorylation of the PDGFR and activation of extracellular signal regulated kinase (ERK1/2), important for growth and survival, were unaltered. Our results suggest that EDG-1 func- tions as an integrator linking the PDGFR to lamellipo- dia extension and cell migration. PDGF, which stimu- lates sphingosine kinase, leading to increased SPP levels in many cell types, also induces translocation of sphingosine kinase to membrane ruffles. Hence, re- cruitment of sphingosine kinase to the cell's leading edge and localized formation of SPP may spatially and temporally stimulate EDG-1, resulting in activation and integration of downstream signals important for direc- tional movement toward chemoattractants, such as PDGF. These results may also shed light on the vital role of EDG-1 in vascular maturation.—Rosenfeldt, H. M., Hobson, J. P., Maceyka, M., Olivera, A., Nava, V. E., Milstien, S., Spiegel, S. EDG-1 links the PDGF receptor to SRC and focal adhesion kinase activation leading to lamellipodia formation and cell migration. FASEB J. 15, 2649 -2659 (2001)