Sphingosine 1-phosphate stimulation of NADPH oxidase activity: relationship with platelet-derived growth factor receptor and c-Src kinase.
This study demonstrates for the first time that sphingosine 1-phosphate (S1P) increases H2O2 production in NIH3T3 fibroblasts through NADPH oxidase activation, confirming the involvement of phosphoinositide-3-kinase and protein kinase C in the activation of this enzyme in non-phagocyte mammalian cells. The results demonstrate also that both platelet-derived growth factor (PDGF) and S1P-mediated NADPH oxidase activation and H2O2 production by Gi-protein coupled receptors (GPCRs) and c-Src kinase. Moreover, both PDGF and S1P activate c-Src kinase through GPCRs, indicating that this kinase can constitute a connection factor between PDGF and S1P signaling, confirming the cross-talk previously found between their receptors. Thus, Gi-protein-mediated NADPH oxidase activation with the consequent H2O2 increase constitutes an early event in the PDGF and S1P pathways. However, a different time course of H2O2 production in S1P-stimulated cells compared to that obtained in PDGF-stimulated cells has been observed, and this seems to be related to the different activation behavior of c-Src kinase induced after S1P or PDGF stimulation. Finally, these data demonstrate that S1P-induced H2O2 production is necessary to maximize c-Src kinase activation, confirming that this is a redox regulated kinase. After which, c-Src plays an important role both upstream and downstream from NADPH oxidase activation.
Catarzi
Serena
S
Department of Biochemical Science, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
Giannoni
Elisa
E
Favilli
Fabio
F
Meacci
Elisabetta
E
Iantomasi
Teresa
T
Vincenzini
Maria T
MT
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019061:src-Family Kinases
D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D043562:Receptors, G-Protein-Coupled; C060506:sphingosine 1-phosphate; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D013110:Sphingosine