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) signal ing pathway, including Pas, Raf, and MAP kinase, are necessary for ner ve growth factor (NGF)-induced neurite outgrowth in PC12 cells. We hav e investigated the role of this pathway in promoting survival of prima ry sympathetic neurons that die when deprived of NGF. NGF caused rapid and sustained increases (approximately 4-fold) in the activities of t he 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 kinas e 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 suppor ts neuronal survival in the absence of NGF. These findings indicate th at activation of MAP kinase is not required for the actions of either cAMP or NGF on neuronal survival.