Endothelin signalling and regulation of protein kinases in glomerular mesangial cells.
The molecular mechanisms of endothelin (ET)-dependent activation of extracellular signal-regulated kinase (ERK)and p38 mitogen-activated protein (MAP) kinase were studied in rat and human renal glomerular mesangial cells. ET-1 induced a rapid and transient activation of Ras in renal mesangial cells, which was dependent upon the formation of the Shc/Grb2/Sos1 signalling complex and resulted in transient ERK activation. We have observed that Pyk2, a calcium-dependent cytoplasmic tyrosine kinase, was expressed in human renal mesangial cells and was tyrosine phosphorylated after ET-1 treatment. ET-1-induced activation of p38 MAPK pathway (but not ERK pathway) was inhibited in human and in rat glomerular mesangial cells expressing dominant-negative form of Pyk2, suggesting the engagement of Pyk2 in ET-1-mediated activation of p38 MAP kinase cascade. Contractive responsiveness of renal mesangial cells was shown to depend on activation of the p38 MAP kinases. Thus, p38 MAP kinase stimulation could perhaps partially account for ET-1 contractive properties, whereas ET-1-induced cell proliferation occurs primarily via Ras-dependent activation of the ERK.
Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, U.S.A. Sorokin@mcw.edu
Andrey
A
Sorokin
Marco
M
Foschi
Michael J
MJ
Dunn
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation; D051418:Focal Adhesion Kinase 2; D005822:Genetic Vectors; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism
D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins