Nerve growth factor-mediated apoptotic pathways

Nerve growth factor-mediated apoptotic pathways are biological signaling cascades through which Nerve Growth Factor (NGF) and its precursor, pro-NGF, regulate programmed cell death (UniProt P01138). While mature NGF typically promotes neuronal survival via the high-affinity Tropomyosin receptor kinase A (TrkA/NTRK1), it can induce apoptosis by binding to the low-affinity p75 neurotrophin receptor (p75NTR/NGFR), especially in the absence of TrkA (PubMed 10455106). Pro-NGF acts as a potent pro-apoptotic ligand by forming a ternary complex with p75NTR and the co-receptor Sortilin, activating c-Jun N-terminal kinase (JNK) and the caspase cascade (PubMed 15565161). These pathways are critically involved in neurodegenerative diseases like Alzheimer's, where elevated pro-NGF contributes to neuronal loss, and in various malignancies such as neuroblastoma and medulloblastoma (PubMed 24787014). Therapeutic agents targeting these pathways include anti-NGF monoclonal antibodies like Tanezumab for chronic pain and Trk inhibitors like Larotrectinib for cancers with NTRK fusions (PubMed 30345907). However, modulating these pathways carries risks, including rapidly progressive osteoarthritis and neurological side effects like dizziness and paresthesia (PubMed 33616662).

Other names

NGF-mediated apoptosisp75NTR-mediated apoptotic signalingpro-NGF/p75NTR/Sortilin pathwayNeurotrophin-mediated cell death

Monoclonal antibodies sequester NGF to prevent receptor activation; small molecule inhibitors block the kinase activity of Trk receptors; p75NTR modulators interfere with pro-apoptotic signaling complexes.