title: SU1498, an inhibitor of vascular endothelial growth factor receptor 2, causes accumulation of phosphorylated ERK kinases and inhibits their activity in vivo and in vitro.
abstract: SU1498, an inhibitor of vascular endothelial growth factor receptor 2, has been used successfully to study the physiological manifestations of receptor functions. Here we report that in addition to its anti-receptor activity, SU1498 stimulates accumulation of phosphorylated ERKs in human umbilical vein endothelial cells and in human aortic endothelial cells in a manner that is dependent on the functioning of the upstream components of the MAPK pathway, B-Raf, and MEK kinases. The enhanced accumulation of phospho-ERKs is observed only in cells that have been stimulated with sphingosine 1-phosphate or protein growth factors; SU1498 by itself is ineffective. We show that the inhibitor acts by blocking the kinase activity of phospho-ERK both in a direct assay and in immunoprecipitates from cells treated with the compound. The data reveal a novel and unique way in which MAPK signaling pathway may be blocked in human endothelial cells.
authors: Methodist Research Institute, Clarian Health Partners, Indianapolis, Indiana 46202, USA.
authors: George
authors: G
authors: Boguslawski
authors: Patrick W
authors: PW
authors: McGlynn
authors: Kevin A
authors: KA
authors: Harvey
authors: A Thomas
authors: AT
authors: Kovala
mesh_terms: D001011:Aorta / Q000473:pathology; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D002934:Cinnamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D010766:Phosphorylation; D011233:Precipitin Tests; D015398:Signal Transduction; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D002934:Cinnamates; D004791:Enzyme Inhibitors; C483044:SU 1498; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases