title: Src tyrosine kinase mediates endothelin-1-induced early growth response protein-1 expression via MAP kinase-dependent pathways in vascular smooth muscle cells.
abstract: We have previously demonstrated that the non-receptor protein tyrosine kinase (NR-PTK) c-Src is an upstream regulator of endothelin-1 (ET-1) and angiotensin II-induced activation of protein kinase B (PKB) signaling in vascular smooth muscle cells (VSMCs). We have also demonstrated that ET-1 potently induces the expression of the early growth response protein-1 (Egr-1), a zinc finger transcription factor that is overexpressed in models of vascular diseases, such as atherosclerosis. However, the involvement of c-Src in ET-1‑induced Egr-1 expression has not yet been investigated and its role in mitogen-activated protein kinase (MAPK) signaling remains controversial. Therefore, the aim of the present study was to examine the role of c-Src in the ET-1-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38 MAPK, 3 key members of the MAPK family and in the regulation of Egr-1 expression in rat aortic A10 VSMCs. ET-1 rapidly induced the phosphorylation of MAPKs, as well as the expression of Egr-1; however, treatment of the VSMCs with PP2, a specific pharmacological inhibitor of c-Src, dose-dependently reduced the phosphorylation of the 3 MAPKs and the expression of Egr-1 induced by ET-1. Furthermore, in mouse embryonic fibroblasts (MEFs) deficient in c-Src (SYF), the ET-1-induced Egr-1 expression and MAPK phosphorylation were significantly suppressed, as compared to MEFs expressing normal Src levels. These results suggest that c-Src plays a critical role in mediating ET-1-induced MAPK phosphorylation and Egr-1 expression in VSMCs.
authors.affiliation: Laboratory of Cellular Signaling, Montreal Diabetes Research Center, Research Center - University of Montreal Hospital Center, Montreal, QC H2X 0A9, Canada.
authors.forename: Estelle R
authors.initials: ER
authors.lastname: Simo-Cheyou
authors.affiliation: Laboratory of Cellular Signaling, Montreal Diabetes Research Center, Research Center - University of Montreal Hospital Center, Montreal, QC H2X 0A9, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Vardatsikos
authors.affiliation: Laboratory of Cellular Signaling, Montreal Diabetes Research Center, Research Center - University of Montreal Hospital Center, Montreal, QC H2X 0A9, Canada.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051766:Early Growth Response Protein 1; D019332:Endothelin-1; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases