Nerve growth factor (NGF) is one of a family of neurotrophins that induce the survival and proliferation of neurons. In cell culture NGF induces the formation of neurite projections and in vivo may stimulate the innervation of tissues. NGF plays a role in the repair, regeneration, and protection of neurons, and as such could serve as a therapeutic agent in neurodegenerative conditions such as Alzheimer's disease. One potential method of NGF application would be through gene therapy or through implantation of cells that have been genetically modified ex vivo. NGF has also been suggested to play a role in other physiological systems and tissues such as the immune system. NGF has two receptors, TrkA and the p75(NTR). NGF may signal its neuroprotective actions through the tyrosine kinase TrkA receptor and trigger apoptosis in some cells through the p75 receptor. High-affinity binding of NGF requires both TrkA and p75(NTR). Binding of NGF to the TrkA receptor causes activation of the receptor tyrosine kinase and downstream signaling cascades. One of the downstream signaling pathways of NGF activates phospholipase C, releasing DAG and IP3 and activating associated downstream pathways such as protein kinase C. Another NGF-activated pathway is the ras-mediated activation of the map kinase pathway. This pathway is initiated through recruitment and activation of Shc, which leads to ras activation through Grb-2 and Sos-1. The Map kinase cascade includes raf, Mek and Erk. The downstream effectors of the ras pathway include activation of fos and jun to form AP-1, activating genes through this transcription factor. Other transcription factors involved in NGF responses include Egr and CREB. The Egr family of transcription factors as well as the Mek/Erk pathway contribute to NGF-induced neurite formation. The CREB family of transcription factors are involved in NGF-induced survival of sympathetic neurons. Further understanding of NGF signaling may be applied to the modulation of NGF responses in neurodegenerative conditions.
