The role of rab proteins in neuronal cells and in the trafficking of neurotrophin receptors

Abstract

Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways.

Figure 1

Signal transduction pathways activated by neurotrophins. Mature neurotrophins bind to their preferred Trk receptors (TrkA for NGF, TrkB for BDNF and NT4/5 and TrkC for NT3) and induce receptor dimerization and phosphorylation at specific tyrosine residues. The phosphorylation of Trk receptors activates three major signaling pathways: the PI3K, Ras and PLC-γ1 pathways. PI3K, via AKT kinase, promotes neuronal survival; Ras activates PI3K and MAPK and induces neuronal differentiation; PLC-γ1 leads to production of IP3 and DAG, the first promoting calcium release from internal stores, which is important for synaptic plasticity, and the second carrying out PKC activation, thus inducing synaptic and neuronal structural plasticity. All of these pathways are also activated by binding of neurotrophins to heterodimers formed by Trk and p75NTR. Cell survival is also promoted by the activation of NFkB induced by the binding of neurotrophin to p75NTR, while apoptosis is induced by neurotrophins binding to the p75NTR-sortilin complex, which activate JNK and NRIF.

Figure 2

Regulation of neurotrophin receptor trafficking by Rab GTPases. Neurotrophins bind to their receptors at the axonal terminal. After binding, receptors are activated and the activated complexes are internalized into Rab5-, Rab21- and Rab22-positive early endosomes (EEs), which are also called signaling endosomes because, in these vesicles, signaling continues and is able to activate cascade pathways that promote neurite outgrowth and dendritic branching. Signaling endosomes undergo a Rab conversion mechanism (Rab5 is replaced by Rab7) and are retrogradely transported along the axon toward the cell body to Rab7-positive late endosomes (LEs). This retrograde transport on microtubules is mediated by the dynein-dynactin motor complex. LEs are also signaling organelles that promote modulation of gene expression in the nucleus. Neurotrophin receptors after synthesis are inserted into the plasma membrane of dendrites and the cell body, where they can bind the ligand and induce dendritic branching. In the absence of neurotrophins, receptors are transcytosed via Rab11-positive recycling endosomes (REs) and reach the axonal termini via anterograde transport mediated by kinesin-1 on microtubule rails.