Nerve growth factor promotes the survival of sympathetic neurons through the cooperative function of the protein kinase C and phosphatidylinositol 3-kinase pathways.

The signaling pathways activated by nerve growth factor (NGF) that account for its ability to promote the survival of neurons are not completely understood. Phosphatidylinositol 3-kinase (PI3K) is critical for the survival of several cell types, including neurons. To determine whether additional signaling pathways cooperate with PI3K to promote survival, we examined other pathways known to be activated by NGF. NGF activated protein kinases C (PKCs) in sympathetic neurons, and pharmacologic PKC activation rescued neurons from apoptosis induced by the withdrawal of NGF. Inhibition of PKCs did not inhibit the survival of NGF-maintained neurons. Similarly, inhibition of PI3K caused only a modest attrition of neurons in the presence of NGF. In contrast, the simultaneous inhibition of both PKCs and PI3K induced the apoptotic death of NGF-maintained sympathetic neurons. Inhibition of both PI3K and PKCs promoted the expression and phosphorylation of the proapoptotic transcription factor c-Jun, indicating that these pathways inhibit programmed cell death at the stage of proapoptotic gene expression. In culture conditions under which PI3K inhibition alone kills NGF-maintained neurons, PKC inhibition also led to a significant loss of viability, indicating that both pathways are required. Therefore, PKC and PI3K, regardless of the culture conditions, cooperate to promote the NGF-dependent survival of sympathetic neurons.