Signaling Control by Compartmentalization Along the Endocytic Route

Many different receptors systems are regulated by endomembrane traffic, including signals from receptors activated by extracellular cues such as receptor tyrosine kinases, G protein-coupled receptors, morphogen receptors, and immune receptors. Notably, each receptor system is uniquely regulated by membrane internalization of receptor-ligand signaling complexes, and traffic to a variety of endosomal compartments. The canonical view of regulation of receptor signaling by endocytosis involves downregulation of receptors by receptor sequestration from the extracellular milieu rich in ligands, or degradation of receptor-ligand complexes following traffic to the lysosome. However, it has become apparent that a wide variety of receptors and their downstream signals exhibit actions unique to specific endomembrane compartments. As such, regulated endocytosis and membrane traffic defines not only the duration and magnitude of signaling, but also allows activation of distinct signaling events in a spatially defined manner, thus specifying unique cellular outcomes.

Recent emerging work has illuminated the requirement for spatial organization of receptor signaling along the endomembrane system. For example, clathrin structures at the plasma membrane serve as signaling hubs, in addition to endocytic portals. A subset of signaling specific clathrin structures is required for activation of PI3K-Akt signaling by the epidermal growth factor receptor (EGFR) and for MAPK activation by some GPCRs. Interestingly, the regulation of receptor signaling by membrane traffic extends well beyond receptor tyrosine kinases and G protein-coupled receptors, and also occurs for integrins that play a key role in anoikis avoidance. Moreover, some recent systematic analysis using proximity biotinylation of signal organization along the endomembrane system have revealed some important new insights into the spatial organization of signaling of GPCRs.

The reciprocal regulation of membrane traffic and signaling as an emerging paradigm is well appreciated. However, some recent advances in understanding the molecular mechanisms by which this regulation occurs, as well as systematic analysis of spatiotemporal signal organization are revealing key new insight into receptor signaling. This Research Topic hopes to bring together a wide range of leading experts in signaling by specific receptor and signaling complexes and highlights how the properties and outcomes of each signaling system is defined by spatial and temporal organization with respect to the endomembrane system. While the concept of regulation of receptor signaling by membrane traffic was first proposed nearly 25 years ago, this Research Topic is timely given the renewed interest in this phenomenon in recent literature, in particular with the identification of novel mechanisms by which signaling is spatially controlled, and the emergence of new modeling approaches to probe these hypotheses and recent systematic studies of protein interactions and cellular organization. This Research Topic will thus examine emerging mechanisms by which signaling is controlled by multiscale (nano- to micron-scale) spatiotemporal organization of signals along the endomembrane system, from the plasma membrane to a myriad of cellular locales.