Gi-mediated activation of the Syk kinase by the receptor mimetic basic secretagogues of mast cells: role in mediating arachidonic acid/metabolites release.
Syk kinase is essential for FcepsilonRI-mediated signaling and release of inflammatory mediators from mast cells. We now show that activation of rat peritoneal mast cells by the nonimmunological, G(i)-mediated pathway also results in the activation of Syk. We show that compound 48/80 (c48/80), a receptor analogue that activates directly G proteins, activates Syk in a pertussis toxin-sensitive fashion. We further show that Syk activation by c48/80 is blocked by the protein kinase C inhibitor GF109203X, by the phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002, by EGTA, and by the selective src-like kinase inhibitor PP1. These results suggest that in the nonimmunological, G(i)-mediated pathway, Syk is located downstream from phospholipase C and phosphatidylinositol 3-kinase. However, in common with the FcepsilonRI-mediated pathway, activation of Syk by c48/80 is dependent on a src-like protein tyrosine kinase. Finally, we show that in the nonimmunological pathway, Syk plays a central role in the release of arachidonic acid/eicosanoid metabolites, but not in the release of prestored mediators such as histamine.
Shefler
I
I
Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Sagi-Eisenberg
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R
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005089:Exocytosis / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines; D051381:Rats; D017208:Rats, Wistar; D017455:Receptors, IgE / Q000502:physiology; D000072377:Syk Kinase; D015533:Transcriptional Activation / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D003189:p-Methoxy-N-methylphenethylamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019061:src-Family Kinases / Q000502:physiology
D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D011799:Quinazolines; D017455:Receptors, IgE; D020032:Tyrphostins; D010566:Virulence Factors, Bordetella; C101044:RTKI cpd; D016718:Arachidonic Acid; D003189:p-Methoxy-N-methylphenethylamine; D037342:Pertussis Toxin; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; D019061:src-Family Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium