title: Sphingosine 1-phosphate transactivates the platelet-derived growth factor beta receptor and epidermal growth factor receptor in vascular smooth muscle cells.
abstract: 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 beta receptor (PDGFbetaR) and EGFR are tyrosine phosphorylated in response to S1P in rat aortic vascular smooth muscle cells (VSMCs). S1P-stimulated transactivation of PDGFbetaR and EGFR was mediated via Gi-coupled EDG receptors. S1P-stimulated transactivation of EGFR and PDGFbetaR 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 PDGFbetaR 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 PDGFbetaR activation in VSMCs that may have important implications for the vessel response to injury.
authors.affiliation: Center for Cardiovascular Research, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tanimoto
authors.forename: Andreea O
authors.initials: AO
authors.lastname: Lungu
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000818:Animals; D001011:Aorta; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008563:Membrane Lipids / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D008246:Lysophospholipids; D008563:Membrane Lipids; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D020797:Receptor, Platelet-Derived Growth Factor beta; D013110:Sphingosine; D013481:Superoxides; D020032:Tyrphostins; C106250:6,7-dimethoxy-3-phenylquinoxaline; C101044:RTKI cpd; C060506:sphingosine 1-phosphate; C494920:Akt1 protein, rat