A mechanism by which the new8 growth factor (NGF) signal is transduced to the nucleus to induce gene expression has been characterized. An NGF-inducible, Ras-dependent protein kinaae has been identified that catalyzes the phosphorylation of the cyclic AMP response element-blndlng protein (CREB) at Ser-133. Phosphorylation of Ser-133 stimulates the ability of CREB to activate tmnscription in NGF-treated cells. These flndlngs auggest that CREB has a more wlda spread function than previously believed and functions in the nucleus as a geneml mediator of growth factor responses. introduction

Nerve growth factor (NGF) and the other members of the neurotrophin family, brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5) have profound effects on neurons, including the promotion of survival and differentiation of distinct but overlapping populations of neurons within the peripheral and central nervous systems (reviewed by Lo, 1992). However, the mechanisms by which the neurotrophins exert these effects on neurons remain incompletely understood. Current understanding of these mechanisms has come in large part from studies of NGF action on the pheochromocytoma cell line PC12 (reviewed by Greene and Tischler, 1982; Halegoua et al., 1990). Upon exposure to NGF, PC12 cells differentiate into sympathetic neuron-like cells. The phenotypic changes that are induced by NGF result from the interaction of NGF with its receptor, Trk, and from the intracellular biochemical events that occur subsequent to receptor activation (Loeb et al., 1991; Hempstead et al., 1992). Trk is a receptor tyrosine kinase whose activity is stimulated by the binding of NGF (Klein etal., 1991; Kaplanet al., 1991). Onceactivated, Trkstimulates the activity of the small GTP-binding protein Ras via a pathway that has not been completely elucidated (Qiu and Green, 1991). Activated Ras then triggers a cascade of phosphorylation events that leads to the activation of mitogen-activated protein (MAP) kinase kinase (MEK), MAP kinase, and ribosomal S8 kinase pp90RSK (Thomas et al., 1992; Wood et al., 1992). Although several cytoplasmic substrates fbr NGF-inducible kinases have been de-