Endocytosis and signaling

Many cellular signaling processes are governed by endocytosis through the internalization of plasma membrane receptors. This receptor clearance defines the quality with which a cell can react to extracellular stimuli. However, growing evidence indicates that endocytosis also enables the formation of endosome-specific signal transduction complexes. Their activity is controlled by the balanced trafficking of receptors and signaling molecules through the endocytic compartments. These are commonly divided into early endosomes, recycling endosomes, and late endosomes. Recent progress has been made in the understanding of the biogenesis of these organelles, highlighting their dynamic interconversion, maturation and also the generation of heterogenous subdomains on their surface. These multifunctional compartments represent the physical basis for the assembly and turnover of signaling complexes, which in turn themselves can define specialized endosomal-signaling platforms.

Introduction

Signal transduction processes connect the recognition of environmental information to the appropriate cellular response. Plasma membrane receptors transfer the extracellular stimuli to the cellular interior and initiate signaling cascades that finally result in a physiological response. The competence of a cell to recognize a specific stimulus depends on the density of the corresponding receptors on the cell surface. Uptake into the intracellular endocytic system by receptor-mediated endocytosis has classically been associated with cell desensitization, but it is now clear that this mechanism can also have signal-propagating functions. Receptors that are activated upon binding of the extracellular ligand subsequently undergo post-translational modifications, such as phosphorylation or ubiquitination on their cytoplasmic side. The activated and modified receptors attract adaptor proteins that function in signaling or internalization. Endocytosed receptors are shuttled to early endosomes, commonly regarded as a central sorting station (Figure 1a). If the cell needs to stay desensitized for certain cues, the responsive receptors are sorted to late endosomes and finally to the lysosome for degradation. In case the cell needs to be resensitized for the corresponding stimulus, the receptor is shuttled back to the plasma membrane directly or via recycling endosomes [1, 2].

This general model already indicates the interdependence of endocytosis and signaling events. However, signal propagation is not restricted to the plasma membrane and may also take place en route, while the receptor shuttles through the endocytic compartments. Endosomes marked with distinct signaling molecules are linked to specific pathways and thus function as context-defined signaling platforms. The findings that, depending on the presence of different signaling complexes, endosomes exist in selected functional states have led to the concept of the signaling endosome [1, 2]. This model has focused on early endosomes in the first place, but recent years have seen a subsequent growth in the evidence that also the other endocytic compartments not only represent intermediate sorting stations but also harbor specific signaling devices, which enables them to perform distinct signaling performance in their own right. This article is not intended as a comprehensive review of the endocytosis field. Rather we aim to highlight recent publications and emerging common themes with the focus on compartmentalized organization of signaling routes.