Mitogen-activated protein kinase-independent pathways mediate the effects of nerve growth factor and cAMP on neuronal survival.
Components of the mitogen-activated protein kinase (MAP kinase) signaling pathway, including Ras, Raf, and MAP kinase, are necessary for nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. We have investigated the role of this pathway in promoting survival of primary sympathetic neurons that die when deprived of NGF. NGF caused rapid and sustained increases (approximately 4-fold) in the activities of the ERK-1 and ERK-2 isoforms of MAP kinase. PD 098059, an inhibitor of MAP kinase kinase activation, blocked the effects of NGF on both kinase isoforms. However, PD 098059 did not attenuate the effects of NGF on neuronal survival. In addition, MAP kinase activity was not increased by chlorophenylthio-cAMP, a cell-permeable analog of cAMP that supports neuronal survival in the absence of NGF. These findings indicate that activation of MAP kinase is not required for the actions of either cAMP or NGF on neuronal survival.
Creedon
D J
DJ
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Johnson
E M
EM
Lawrence
J C
JC
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D005728:Ganglia, Sympathetic; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D004676:Myelin Basic Protein / Q000378:metabolism; D009414:Nerve Growth Factors / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D047428:Protein Kinase Inhibitors; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D005419:Flavonoids; D004676:Myelin Basic Protein; D009414:Nerve Growth Factors; D047428:Protein Kinase Inhibitors; D000242:Cyclic AMP; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one