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 NGF Pathway

Nerve growth factor (NGF) is a member of the neurotrophin family that also includes brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT4/5) and neurotrophin-6 (NT-6). Neurotrophins are small secretory proteins that promote cell growth, differentiation and survival in the central and peripheral nervous system. NGF and other members of the neurotrophin family bind to two types of membrane receptors; the p75(NTR) (p75NGFR) (p75 neurotrophin receptor) receptor, a member of the TNF receptor/Fas/CD40 superfamily, and members of the TRK (p145trk) family of tyrosine kinase receptors. NGF binds specifically to TRKA (p140trkA). BDNF and NT-4 bind p145trkB and neurotrohin-3 binds p145trkC. All four neurotrophins bind p75NTR with low affinity.

NGF binding to Trk typically signals neural cell survival and differentiation through activation of numerous signaling pathways that include the small G proteins; Ras, Rap-1, and the Cdc42-Rac-Rho family, PI-3-kinase and phospholipase Cgamma (PLCgamma). The binding of NGF to TrkA is required for the survival of target cells. NGR also binds to p75(NTR) with consequences that depend upon the relative expression of TrkA and p75(NTR) and cell context. In the absence of TrkA, NGR binding to p75(NTR) typically leads to apoptosis. When TrkA is present, p75(NTR) has a variety of functions, including enhancement of the TrkA mediated signals. A general role of p75(NTR) appears to involve a “quality control” function. P75(NTR) promotes programmed cell death (PCD) when NGF is withdrawn; cells are exposed to mismatched neurotrophins; immature cells are inappropriately exposed to neurotrophins, or cells are exposed to unprocessed neurotrophins. P75 is a receptor for beta-amyloid which potentially links NGF and this receptor to Alzheimer’s disease (AD).