This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 94/8/1050    most recent 01.RES.0000126404.41421.BEv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanimoto, T. Articles by Berk, B. C. Search for Related Content PubMed PubMed Citation Articles by Tanimoto, T. Articles by Berk, B. C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Growth factors/cytokines Smooth muscle proliferation and differentiation Signal transduction

Sphingosine 1-Phosphate Transactivates the Platelet-Derived Growth Factor ß Receptor and Epidermal Growth Factor Receptor in Vascular Smooth Muscle Cells

From the Center for Cardiovascular Research, University of Rochester, Rochester, NY.

Correspondence to Bradford C. Berk, Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail bradford_berk{at}urmc.rochester.edu

Sphingosine 1-phosphate (S1P) is a bioactive lipid generated during vascular injury that regulates cell growth, differentiation, survival, and motility via endothelial differentiation gene (EDG) family G protein–coupled receptors. Although several G protein–coupled receptor ligands transactivate receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), S1P-stimulated receptor tyrosine kinase transactivation has not been well studied. We show that platelet-derived growth factor ß receptor (PDGFßR) and EGFR are tyrosine phosphorylated in response to S1P in rat aortic vascular smooth muscle cells (VSMCs). S1P-stimulated transactivation of PDGFßR and EGFR was mediated via Gi-coupled EDG receptors. S1P-stimulated transactivation of EGFR and PDGFßR was dependent on Src, reactive oxygen species, and cholesterol-rich membranes. A phosphoinositide 3-kinase–Akt pathway was activated by S1P and blocked by AG1296 and AG1478. Activation of extracellular signal–regulated kinase (ERK) 1 and ERK2 pathway by S1P was blocked only by AG1478. In Chinese hamster ovary cells that expressed exogenous EDG-1, activation of Akt and ERK1/2 in response to S1P was observed and was enhanced by coexpression of PDGFßR or EGFR. S1P-mediated VSMC proliferation was shown to be secondary to transactivation, because it was suppressed by AG1296 and AG1478. These data establish S1P as an important stimulus for EGFR and PDGFßR activation in VSMCs that may have important implications for the vessel response to injury.

Key Words: signal transduction • epidermal growth factor • sphingosine 1-phosphate

This article has been cited by other articles:

				K. Block, A. Eid, K. K. Griendling, D.-Y. Lee, Y. Wittrant, and Y. Gorin Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II: ROLE IN MESANGIAL CELL HYPERTROPHY AND FIBRONECTIN EXPRESSION J. Biol. Chem., August 29, 2008; 283(35): 24061 - 24076. [Abstract] [Full Text] [PDF]

				L. Albanito, D. Sisci, S. Aquila, E. Brunelli, A. Vivacqua, A. Madeo, R. Lappano, D. P. Pandey, D. Picard, L. Mauro, et al. Epidermal Growth Factor Induces G Protein-Coupled Receptor 30 Expression in Estrogen Receptor-Negative Breast Cancer Cells Endocrinology, August 1, 2008; 149(8): 3799 - 3808. [Abstract] [Full Text] [PDF]

				C. K. Means, S. Miyamoto, J. Chun, and J. H. Brown S1P1 Receptor Localization Confers Selectivity for Gi-mediated cAMP and Contractile Responses J. Biol. Chem., May 2, 2008; 283(18): 11954 - 11963. [Abstract] [Full Text] [PDF]

				K. Omori, Y. Shikata, K. Sarai, N. Watanabe, J. Wada, N. Goda, N. Kataoka, K. Shikata, and H. Makino Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1523 - C1531. [Abstract] [Full Text] [PDF]

				M. Koide, P. L. Penar, B. I. Tranmer, and G. C. Wellman Heparin-binding EGF-like growth factor mediates oxyhemoglobin-induced suppression of voltage-dependent potassium channels in rabbit cerebral artery myocytes Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1750 - H1759. [Abstract] [Full Text] [PDF]

				S. Langlois, C. Nyalendo, G. Di Tomasso, L. Labrecque, C. Roghi, G. Murphy, D. Gingras, and R. Beliveau Membrane-Type 1 Matrix Metalloproteinase Stimulates Cell Migration through Epidermal Growth Factor Receptor Transactivation Mol. Cancer Res., June 1, 2007; 5(6): 569 - 583. [Abstract] [Full Text] [PDF]

				D. H. Walter, U. Rochwalsky, J. Reinhold, F. Seeger, A. Aicher, C. Urbich, I. Spyridopoulos, J. Chun, V. Brinkmann, P. Keul, et al. Sphingosine-1-Phosphate Stimulates the Functional Capacity of Progenitor Cells by Activation of the CXCR4-Dependent Signaling Pathway via the S1P3 Receptor Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 275 - 282. [Abstract] [Full Text] [PDF]

				J.-J. Liao, M.-C. Huang, M. Graler, Y. Huang, H. Qiu, and E. J. Goetzl Distinctive T Cell-suppressive Signals from Nuclearized Type 1 Sphingosine 1-Phosphate G Protein-coupled Receptors J. Biol. Chem., January 19, 2007; 282(3): 1964 - 1972. [Abstract] [Full Text] [PDF]

				M. Yadav, L. Clark, and J. S. Schorey Macrophage's Proinflammatory Response to a Mycobacterial Infection Is Dependent on Sphingosine Kinase-Mediated Activation of Phosphatidylinositol Phospholipase C, Protein Kinase C, ERK1/2, and Phosphatidylinositol 3-Kinase J. Immunol., May 1, 2006; 176(9): 5494 - 5503. [Abstract] [Full Text] [PDF]

				O. Sukocheva, C. Wadham, A. Holmes, N. Albanese, E. Verrier, F. Feng, A. Bernal, C. K. Derian, A. Ullrich, M. A. Vadas, et al. Estrogen transactivates EGFR via the sphingosine 1-phosphate receptor Edg-3: the role of sphingosine kinase-1 J. Cell Biol., April 24, 2006; 173(2): 301 - 310. [Abstract] [Full Text] [PDF]

				Y. Fujita, M. Yoshizumi, Y. Izawa, N. Ali, H. Ohnishi, Y. Kanematsu, K. Ishizawa, K. Tsuchiya, and T. Tamaki Transactivation of Fetal Liver Kinase-1/Kinase-Insert Domain-Containing Receptor by Lysophosphatidylcholine Induces Vascular Endothelial Cell Proliferation Endocrinology, March 1, 2006; 147(3): 1377 - 1385. [Abstract] [Full Text] [PDF]

				J. S. Kang, Y. D. Yoon, M. H. Han, S.-B. Han, K. Lee, K. H. Lee, S.-K. Park, and H. M. Kim Glabridin Suppresses Intercellular Adhesion Molecule-1 Expression in Tumor Necrosis Factor-{alpha}-Stimulated Human Umbilical Vein Endothelial Cells by Blocking Sphingosine Kinase Pathway: Implications of Akt, Extracellular Signal-Regulated Kinase, and Nuclear Factor-{kappa}B/Rel Signaling Pathways Mol. Pharmacol., March 1, 2006; 69(3): 941 - 949. [Abstract] [Full Text] [PDF]

				C. Akekawatchai, J. D. Holland, M. Kochetkova, J. C. Wallace, and S. R. McColl Transactivation of CXCR4 by the Insulin-like Growth Factor-1 Receptor (IGF-1R) in Human MDA-MB-231 Breast Cancer Epithelial Cells J. Biol. Chem., December 2, 2005; 280(48): 39701 - 39708. [Abstract] [Full Text] [PDF]

				S. K. Goparaju, P. S. Jolly, K. R. Watterson, M. Bektas, S. Alvarez, S. Sarkar, L. Mel, I. Ishii, J. Chun, S. Milstien, et al. The S1P2 Receptor Negatively Regulates Platelet-Derived Growth Factor-Induced Motility and Proliferation Mol. Cell. Biol., May 15, 2005; 25(10): 4237 - 4249. [Abstract] [Full Text] [PDF]

				J. H. Finigan, S. M. Dudek, P. A. Singleton, E. T. Chiang, J. R. Jacobson, S. M. Camp, S. Q. Ye, and J. G. N. Garcia Activated Protein C Mediates Novel Lung Endothelial Barrier Enhancement: ROLE OF SPHINGOSINE 1-PHOSPHATE RECEPTOR TRANSACTIVATION J. Biol. Chem., April 29, 2005; 280(17): 17286 - 17293. [Abstract] [Full Text] [PDF]

				T. Djordjevic, R. S. BelAiba, S. Bonello, J. Pfeilschifter, J. Hess, and A. Gorlach Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 519 - 525. [Abstract] [Full Text] [PDF]

				R. P. Brandes and J. Kreuzer Vascular NADPH oxidases: molecular mechanisms of activation Cardiovasc Res, January 1, 2005; 65(1): 16 - 27. [Abstract] [Full Text] [PDF]

				K. Lockman, J. S. Hinson, M. D. Medlin, D. Morris, J. M. Taylor, and C. P. Mack Sphingosine 1-Phosphate Stimulates Smooth Muscle Cell Differentiation and Proliferation by Activating Separate Serum Response Factor Co-factors J. Biol. Chem., October 8, 2004; 279(41): 42422 - 42430. [Abstract] [Full Text] [PDF]

				I. Tegeder and G. Geisslinger Opioids As Modulators of Cell Death and Survival--Unraveling Mechanisms and Revealing New Indications Pharmacol. Rev., September 1, 2004; 56(3): 351 - 369. [Abstract] [Full Text] [PDF]