7 - Nerve Growth Factors

Abstract

Nerve growth factor (NGF) together with brain-derived neurotrophic factor (BDNF) and the neurotrophins constitute the neurotrophin family of growth factors. NTs play a wide variety of roles such as in neural differentiation, survival of neuronal cells, and neuroprotection and repair. NTs upon receptor binding activate the conventional signaling pathways, namely Ras/ERK/MAPK and PI3K/Akt, leading to cell survival and differentiation-related functions. Three Trk receptors have been identified, TrkA, TrkB, and TrkC, which carry differential binding abilities for the neurotrophins. TrkA binds NGF, TrkB binds BDNF and NT4, and TrkC binds NT3. Heterodimers of TrkA and p75NGFR promote cell survival but homodimers of p75NGFR lead to apoptosis. NGF, presumably mediated by TrkA, promotes the formation of a complex between the nuclear speckle protein acinus and CtBP2, which leads to the downregulation of cyclin D1 and the inhibition of cell proliferation in leukemic cells. The binding of mature NTs to Trks signals through Ras/MAPK or PI3/Akt, which leads to cell survival. Ligand binding to p75NGFR leads to neural cell death with JNK and p53 mediation. NGF is expressed in most esophageal squamous cell carcinomas, and expression levels correlate with tumor stage, the presence of metastatic tumor and poor prognosis. It is frequently expressed in the tumor component of breast cancers. TrkA is expressed in breast cancer cell lines. Overexpression of the receptor leads to enhanced growth, induction of angiogenesis, and metastasis of breast cancer cells xenografted into immune compromised mice.