Redox regulation of platelet-derived-growth-factor-receptor: role of NADPH-oxidase and c-Src tyrosine kinase.
This study identifies some early events contributing to the redox regulation of platelet-derived growth factor receptor (PDGFr) activation and its signalling in NIH3T3 fibroblasts. We demonstrate for the first time that the redox regulation of PDGFr tyrosine autophosphorylation and its signalling are related to NADPH oxidase activity through protein kinase C (PKC) and phosphoinositide-3-kinase (PI3K) activation and H2O2 production. This event is also essential for complete PDGF-induced activation of c-Src kinase by Tyr416 phosphorylation, and the involvement of c-Src kinase on H2O2-induced PDGFr tyrosine phosphorylation is demonstrated, suggesting a role of this kinase on the redox regulation of PDGFr activation. Finally, it has been determined that not only PI3K activity, but also PKC activity, are related to NADPH oxidase activation due to PDGF stimulation in NIH3T3 cells, as it occurs in non-phagocyte cells. Therefore, we suggest a redox circuit whereby, upon PDGF stimulation, PKC, PI3K and NADPH oxidase activity contribute to complete c-Src kinase activation, thus promoting maximal phosphorylation and activation of PDGFr tyrosine phosphorylation.
Catarzi
Serena
S
Department of Biochemical Sciences, University of Florence, viale Morgagni 50, 50134, Florence, Italy.
Biagioni
Chiara
C
Giannoni
Elisa
E
Favilli
Fabio
F
Marcucci
Tommaso
T
Iantomasi
Teresa
T
Vincenzini
Maria Teresa
MT
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D003593:Cytoplasm / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000502:physiology*; D041681:NIH 3T3 Cells; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D011493:Protein Kinase C; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D013481:Superoxides; D019061:src-Family Kinases