Neurotrophin signaling through the p75 neurotrophin receptor

The neurotrophins are growth factors that play critical roles in the development, maintenance, survival, and death of the nervous system. The signal transducing systems that mediate the diverse biological functions of the neurotrophins are initiated by their interactions with two categories of cell surface receptors, the Trk family of tyrosine kinases and the p75 neurotrophin receptor (p75NTR). While the Trk receptors are responsible for most of the survival and growth properties of the neurotrophins, the actions of p75NTR fall into two categories. First, p75NTR is a Trk co-receptor that can enhance or suppress neurotrophin-mediated Trk receptor activity. Second, p75NTR autonomously activates signaling cascades that result in the induction of apoptosis or in the promotion of survival. The signaling cascades activated by p75NTR remain elusive, but structural and functional differences between p75NTR and other tumor necrosis factor receptor (TNFR) superfamily members suggest that p75NTR employs distinct signaling pathways. p75NTR has been shown to activate the NF-kappaB, Akt, and JNK pathways and interacts with several adaptor proteins. Of these, NRAGE, NADE, and NRIF have been associated with the induction of apoptosis, and FAP-1, RIP2, and TRAF6 appear to promote cellular survival. It remains a major challenge to link the various p75NTR binding proteins to specific p75NTR-dependent functions, but the identification of p75NTR interactors and signaling pathways has sparked new directions in p75NTR research, and will provide a better understanding of this enigmatic receptor.