Biogenesis and function of the NGF/TrkA signaling endosome

Abstract

Target-derived neurotrophin nerve growth factor (NGF) and its receptor TrkA are well known for retrograde signaling to promote survival and innervation of sympathetic and sensory neurons. In recent years, the signaling endosome model has been used to describe the sustained NGF/TrkA retrograde signaling as a process of endocytosis and retrograde transport of NGF/TrkA-containing endosomes from the axon terminal to the cell body for activation of NGF-inducible gene expression responsible for neuronal survival and development. Here, we review the biogenesis and function of NGF, TrkA, and the signaling endosome and discuss possible roles of Rab GTPases in the biogenesis and trafficking of signaling endosomes.

Keywords: Endocytosis; Membrane trafficking; NGF; Neurotrophin; Rab; Retrograde transport; Signaling endosome; TrkA.

Figure 1

Anterograde and retrograde trafficking of TrkA-containing endosomes in neurons. The upper panel illustrates anterograde transport of newly synthesized TrkA (blue bars) from the soma to the axonal growth cone, via exocytic or transcytotic pathway. Upon glycosylation and packaging into Golgi (Green)-derived transport vesicles (red), TrkA is either transported directly along the axon to the growth cone or trafficked locally to the somatodendritic plasma membrane first, followed by transcytosis to the axonal growth cone. The lower panel illustrates retrograde transport of TrkA upon binding and activation by target-derived NGF (purple spheres), from the axonal growth cone to the soma. NGF/TrkA is endocytosed and incorporated into endocytic vesicles (orange) to be trafficked locally for recycling or for retrograde transport to the soma. The signaling endosome hypothesis suggests that these long-lived retrograde endosomes remain liganded and continue signaling in the axon and at the soma for trafficking and activation of gene expression essential for neuronal survival and development. (For interpretation of the references to color in this figure legend, the reader is referred to the online version of this book.)

Figure 2

NGF/TrkA signal transduction pathways in survival and differentiation of neurons. TrkA (blue bars) signaling is best characterized for activation of MAPK, PI3K and PLC γ pathways mediated mainly by the phosphorylation (black spheres) of two tyrosine residues in the cytoplasmic domain, Tyr490 (Y490) and Tyr785 (Y785). NGF dimers (purple spheres) bind to the extracellular ligand-binding domain of two TrkA monomers promoting homodimerization, activation of the tyrosine kinase domain in the activation loop, and trans-phosphorylation of Y490 and Y785. Phosphorylation of these residues recruits pro-differentiation and pro-survival adaptor and signaling molecules and activates the SHC-Ras-MAPK, PI3K-AKT, and PLCγ-PKC signaling pathways. (For interpretation of the references to color in this figure legend, the reader is referred to the online version of this book.)

Figure 3

A model for NGF/TrkA signal endosome. Pincher facilitates the biogenesis of NGF/TrkA signaling endosomes, which recruit the minus-end motor protein dynein to promote retrograde transport on microtubules in the axon. NGF remains bound to TrkA in the signaling endosome and keeps TrkA activated for sustained signaling that facilitates trafficking and leads to neuronal survival and differentiation. Rab5 or Rab22 or other Rabs may regulate the biogenesis and retrograde transport of NGF/TrkA signaling endosomes.