NGF Receptor

NGF Receptor Discovery

In 1980s, studies have revealed that NGF receptor on various neuronal populations and on tumor cell lines were heterogeneous with regard to binding affinity and binding kinetics. Different laboratories have purified two kinds of NGF receptor, NGF receptor proteins of 130-140 kDa and 70-80 kDa. The first NGF receptor to be cloned was the 75-80 kDa protein and was named simply as p75. When expressed in fibroblasts, this receptor had properties similar to the low-affinity and kinetically fast receptors. Then, the observations that NGF stimulates tyrosine kinase activity and that the tissue distribution of transcripts of the receptor tyrosine kinase protooncogene trk was similar to the distribution of NGF-responsive neurons led to the discovery that the encoded protein p140trk is an NGF receptor. This p140trk protein is TrkA that has properties similar to the high-affinity. Further research reveals that NGF binding to p75 is rapidly released by mild trypsin treatment because of the rapid degradation of the NGF binding site while NGF binding to TrkA is stable to trypsin treatment. Then, two cell surface receptors for NGF have been identified: a receptor tyrosine kinase, TrkA, and the low-affinity neurotrophin receptor, p75NTR. NGF exerts its growth- and survival-promoting effects on neurons through activation of TrkA and subsequent biochemical events that ultimately influence the expression of various genes, including those encoding ion channels, neurotransmitter-synthesizing enzymes, and cytoskeletal components.

NGF Receptor Function

TrkA is a ligand-mediated receptor. NGF stimulates dimerization and autophosphorylation of TrkA on tyrosine residues and initiation of intracellular signaling cascades that propagate the signal to the nucleus. Transcription factor becomes phosphorylated on their transcriptional regulatory site, and this phosphorylation event promotes NGF activation of transcription of the immediate early gene. The expression of various genes is influenced and a series of biological response is mediated.

p75 is a NGF receptor as a facilitator of Trk-mediated neuronal survival and as a regulator of neuronal cell death. AS a facilitator of Trk, p75 assumes the role of a coreceptor that refines Trk affinity and specificity for NGF. p75 also influences signaling pathways elicited by Trk activation. For example, p75 can bind Trk adaptor to stimulate its phosphorylation and augment Trk signaling. Trk dimer-p75 receptor complexes possess signaling capacities that are inherently different from those of Trk dimers. There are some mutual binding partners for p75 and TrkA. Upon binding, the ability of NGF to activate distinct signaling pathways is enhanced. In addition to modulating Trk-mediated functions, p75 also controls and conveys Trk-independent activities. Numerous studies have demonstrated that p75, depending on the cellular context, can activate signaling cascades regulating apoptosis, Schwann cell migration, myelination, axonal growth and regeneration.