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Science 291 (5509): 1800-1803

Copyright © 2001 by the American Association for the Advancement of Science

Role of the Sphingosine-1-Phosphate Receptor EDG-1 in PDGF-Induced Cell Motility

John P. Hobson,1* Hans M. Rosenfeldt,1* Larry S. Barak,2 Ana Olivera,1 Samantha Poulton,1 Marc G. Caron,2 Sheldon Milstien,3 Sarah Spiegel1dagger

EDG-1 is a heterotrimeric guanine nucleotide binding protein-coupled receptor (GPCR) for sphingosine-1-phosphate (SPP). Cell migration toward platelet-derived growth factor (PDGF), which stimulates sphingosine kinase and increases intracellular SPP, was dependent on expression of EDG-1. Deletion of edg-1 or inhibition of sphingosine kinase suppressed chemotaxis toward PDGF and also activation of the small guanosine triphosphatase Rac, which is essential for protrusion of lamellipodia and forward movement. Moreover, PDGF activated EDG-1, as measured by translocation of beta -arrestin and phosphorylation of EDG-1. Our results reveal a role for receptor cross-communication in which activation of a GPCR by a receptor tyrosine kinase is critical for cell motility.

1 Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
2 Howard Hughes Medical Institute Laboratories and Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
3 Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, MD 20892, USA
*   These authors contributed equally to this report.

dagger    To whom correspondence should be addressed. E-mail: spiegel{at}bc.georgetown.edu


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Lysophospholipids--Receptor Revelations.
T. Hla, M.-J. Lee, N. Ancellin, J. H. Paik, and M. J. Kluk (2001)
Science 294, 1875-1878
   Abstract »    Full Text »    PDF »
Sphingolipid Mediators in Cardiovascular Cell Biology and Pathology.
T. Levade, N. Auge, R. J. Veldman, O. Cuvillier, A. Negre-Salvayre, and R. Salvayre (2001)
Circ. Res. 89, 957-968
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Tumor Necrosis Factor-alpha Induces Stress Fiber Formation through Ceramide Production: Role of Sphingosine Kinase.
A. N. Hanna, L. G. Berthiaume, Y. Kikuchi, D. Begg, S. Bourgoin, and D. N. Brindley (2001)
Mol. Biol. Cell 12, 3618-3630
   Abstract »    Full Text »    PDF »
Bridging with GAPs: Receptor Communication Through RGS Proteins.
K. M. Druey (2001)
Sci. STKE 2001, re14
   Abstract »    Full Text »    PDF »
Sphingosine-1-Phosphate and the Leading Edg-1 of Vascular Smooth Muscle Cells.
W. Erl and W. Siess (2001)
Circ. Res. 89, 474-476
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Tethering of the Platelet-derived Growth Factor beta Receptor to G-protein-coupled Receptors. A NOVEL PLATFORM FOR INTEGRATIVE SIGNALING BY THESE RECEPTOR CLASSES IN MAMMALIAN CELLS.
F. Alderton, S. Rakhit, K. C. Kong, T. Palmer, B. Sambi, S. Pyne, and N. J. Pyne (2001)
J. Biol. Chem. 276, 28578-28585
   Abstract »    Full Text »    PDF »
Extracellular Export of Sphingosine Kinase-1 Enzyme. SPHINGOSINE 1-PHOSPHATE GENERATION AND THE INDUCTION OF ANGIOGENIC VASCULAR MATURATION.
N. Ancellin, C. Colmont, J. Su, Q. Li, N. Mittereder, S.-S. Chae, S. Stefansson, G. Liau, and T. Hla (2002)
J. Biol. Chem. 277, 6667-6675
   Abstract »    Full Text »    PDF »
Sphingosine 1-Phosphate and Isoform-specific Activation of Phosphoinositide 3-Kinase beta . EVIDENCE FOR DIVERGENCE AND CONVERGENCE OF RECEPTOR-REGULATED ENDOTHELIAL NITRIC-OXIDE SYNTHASE SIGNALING PATHWAYS.
J. Igarashi and T. Michel (2001)
J. Biol. Chem. 276, 36281-36288
   Abstract »    Full Text »    PDF »
Sphingosine-1-Phosphate, a Platelet-Derived Lysophospholipid Mediator, Negatively Regulates Cellular Rac Activity and Cell Migration in Vascular Smooth Muscle Cells.
Y. Ryu, N. Takuwa, N. Sugimoto, S. Sakurada, S. Usui, H. Okamoto, O. Matsui, and Y. Takuwa (2002)
Circ. Res. 90, 325-332
   Abstract »    Full Text »    PDF »
Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration.
M. J. Kluk and T. Hla (2001)
Circ. Res. 89, 496-502
   Abstract »    Full Text »    PDF »

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