Alternate FGF2-ERK1/2 signaling pathways in retinal photoreceptor and glial cells in vitro.
Basic fibroblast growth factor (FGF2) stimulates photoreceptor survival in vivo and in vitro, but the molecular signaling mechanism(s) involved are unknown. Immunohistochemical and immunoblotting analyses of pure photoreceptors, inner retinal neurons, and Müller glial cells (MGC) in vitro revealed differential expression of the high affinity FGF receptors (FGFR1-4), as well as many cytoplasmic signaling intermediates known to mediate the extracellular signal-regulated kinase (ERK1/2) pathway. FGF2-induced tyrosine phosphorylation in vitro exhibited distinct profiles for each culture type, and FGF2-induced ERK1/2 activation was observed for all three preparations. Whereas U0126, a specific inhibitor of ERK kinase (MEK), completely abolished FGF2-induced ERK1/2 tyrosine phosphorylation and survival in cultured photoreceptors, persistent ERK1/2 phosphorylation was observed in cultured inner retinal cells and MGC. Furthermore U0126 treatment entirely blocked nerve growth factor-induced ERK1/2 activation in MGC, as well as FGF2-induced ERK1/2 activation in cerebral glial cells. Taken together, these data indicate that FGF2-induced ERK1/2 activation is entirely mediated by MEK within photoreceptors, which is responsible for FGF2-stimulated photoreceptor survival. In contrast, inner retina/glia possess alternative, cell type, and growth factor-specific MEK-independent ERK1/2 activation pathways. Hence signaling and biological effects elicited by FGF2 within retina are mediated by cell type-specific pathways.
Kinkl
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Laboratoire de Physiopathologie Cellulaire et Moléculaire de la Rétine, INSERM-Université Louis Pasteur EMI 9918, Clinique Médicale A, Centre Hospitalier Régional Universitaire, BP. 426, 1 Place de l'Hôpital, 67091 Strasbourg Cedex, France.
Sahel
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Hicks
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D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D010786:Photoreceptor Cells / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D017468:Receptors, Fibroblast Growth Factor; C113580:U 0126; D016222:Fibroblast Growth Factor 2; D014443:Tyrosine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases