The platelet-derived-growth-factor receptor, not the epidermal-growth-factor receptor, is used by lysophosphatidic acid to activate p42/44 mitogen-activated protein kinase and to induce prostaglandin G/H synthase-2 in mesangial cells.
In renal mesangial cells, activation of protein tyrosine kinase receptors may increase the activity of mitogen-activated protein (MAP) kinases and subsequently induce expression of prostaglandin G/H synthase-2 (PGHS-2, cyclo-oxygenase-2). As examples, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) were shown to transiently enhance p42/44 MAP kinase activity, which was an essential step in the induction of PGHS-2 mRNA and protein. Inhibitors of receptor kinase activities, tyrphostins AG1296 and AG1478, specifically inhibited the effects of PDGF and EGF respectively. Activation of p42/44 and p38 MAP kinases and PGHS-2 induction were also mediated by lysophosphatidic acid (LPA), which binds to pertussis-toxin-sensitive G-protein-coupled receptors. LPA stimulation was inhibited by AG1296, but not AG1478, indicating involvement of the PDGF receptor kinase in LPA-mediated signalling. This was confirmed by pertussis-toxin-sensitive tyrosine phosphorylation of the PDGF receptor by LPA, whereas no phosphorylation of the EGF receptor was detected. For comparison, 5-hydroxytryptamine ('serotonin')-mediated signalling was only partially inhibited by AG1296, and also not affected by AG1478. A strong basal AG1296-sensitive tyrosine phosphorylation of the PDGF receptor and a set of other proteins was observed, which by itself was not sufficient to induce p42/44 MAP kinase activation, but played an essential role not only in LPA- but also in phorbol ester-mediated activation. Taken together, the PDGF receptor, but not the EGF receptor, is involved in LPA-mediated MAP kinase activation and PGHS-2 induction in primary mesangial cells, where both protein kinase receptors are present and functionally active.
Goppelt-Struebe
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M
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, D-91054 Erlangen, Germany. Goppelt-Struebe@rzmail.uni-erlangen.de
Fickel
S
S
Reiser
C O
CO
D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin; D010766:Phosphorylation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D020239:Receptor Cross-Talk; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D007527:Isoenzymes; D008246:Lysophospholipids; D020032:Tyrphostins; D010566:Virulence Factors, Bordetella; C106250:6,7-dimethoxy-3-phenylquinoxaline; D012701:Serotonin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D037342:Pertussis Toxin; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins