Recent advances in understanding neurotrophin signaling

Abstract

The nerve growth factor family of growth factors, collectively known as neurotrophins, are evolutionarily ancient regulators with an enormous range of biological functions. Reflecting this long history and functional diversity, mechanisms for cellular responses to neurotrophins are exceptionally complex. Neurotrophins signal through p75 (NTR), a member of the TNF receptor superfamily member, and through receptor tyrosine kinases (TrkA, TrkB, TrkC), often with opposite functional outcomes. The two classes of receptors are activated preferentially by proneurotrophins and mature processed neurotrophins, respectively. However, both receptor classes also possess neurotrophin-independent signaling functions. Signaling functions of p75 (NTR) and Trk receptors are each influenced by the other class of receptors. This review focuses on the mechanisms responsible for the functional interplay between the two neurotrophin receptor signaling systems.

Keywords: 75 kDa neurotrophin receptor; Spätzle proteins; mature processed neurotrophins; proneurotrophins.

Figure 1.. p75 ^NTR Signaling.

In absence of ligand, death domains of disulfide-linked p75 ^NTR dimer bind RhoGDI, promoting formation of active GTP-bound RhoA. Binding of neurotrophin or proneurotrophin causes a scissoring action of the dimer, displacing the death domains laterally and allowing RIP2 to bind the death domains. RIP2 promotes activation of JNK and NF-κB and by displacing RhoGDI, terminates RhoA activation.

Figure 2.. Cell death and cell survival signaling by p75 ^NTR and Trk receptors.

( Above) Proneurotrophins interact preferentially with p75 ^NTR, promoting JNK dependent caspase activation and cell death. Sequential cleavage of p75 ^NTR by ADAM10/17 and γ-secretase, allowing cytoplasmic mobilization of the intracellular domain of p75 ^NTR, may also promote cell death, by a mechanism that is only indirectly promoted by neurotrophins. Non-liganded Trk A and TrkC promote cell death by a mechanism that implicates the p75 ^NTR cleavage pathway. ( Below) Mature neurotrophins preferentially activate Trk receptors, in a manner that may be enhanced by p75 ^NTR, particularly for TrkA. Neurotrophin activation of Trks promotes cell survival.