The neurotrophin receptor signaling endosome: Where trafficking meets signaling

Abstract

Neurons are the largest cells in the body and form subcellular compartments such as axons and dendrites. During both development and adulthood building blocks must be continually trafficked long distances to maintain the different regions of the neuron. Beyond building blocks, signaling complexes are also transported, allowing for example, axons to communicate with the soma. The critical roles of signaling via ligand-receptor complexes is perhaps best illustrated in the context of development, where they are known to regulate polarization, survival, axon outgrowth, dendrite development, and synapse formation. However, knowing 'when' and 'how much' signaling is occurring does not provide the complete story. The location of signaling has a significant impact on the functional outcomes. There are therefore complex and functionally important trafficking mechanisms in place to control the precise spatial and temporal aspects of many signal transduction events. In turn, many of these signaling events affect trafficking mechanisms, setting up an intricate connection between trafficking and signaling. In this review we will use neurotrophin receptors, specifically TrkA and TrkB, to illustrate the cell biology underlying the links between trafficking and signaling. Briefly, we will discuss the concepts of how trafficking and signaling are intimately linked for functional and diverse signaling outputs, and how the same protein can play different roles for the same receptor depending on its localization. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017.

Keywords: Coronin1a; Rab proteins; Trk receptors; endocytosis; transcytosis.

Figure 1

Internalization and trafficking pathways of TrkA. (1) Constitutive endocytosis and transcytosis to the distal axon before TrkA encounters NGF. (2) TrkA encounters NGF in the distal axon and internalizes into a signaling endosome. The signaling endosomes then traffics retrogradely to the axon. (3) The signaling endosome can then be exocytosed onto the soma membrane and re-internalized during signaling transcytosis. PSD = Postsynaptic Density. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Basics of endosomal sorting. All internalized cargo gets sorted into the early endosome. From the early endosome, cargo sorts into distinct compartments which then bud off to form recycling endosomes (Rab4, Rab11), or late endosomes (Rab7) which mature into lysosomes, or sort back to the TGN through retromer. [Color figure can be viewed at wileyonlinelibrary.com]