Endocytosis and signalling: intertwining molecular networks

Abstract

Cell signalling and endocytic membrane trafficking have traditionally been viewed as distinct processes. Although our present understanding is incomplete and there are still great controversies, it is now recognized that these processes are intimately and bidirectionally linked in animal cells. Indeed, many recent examples illustrate how endocytosis regulates receptor signalling (including signalling from receptor tyrosine kinases and G protein-coupled receptors) and, conversely, how signalling regulates the endocytic pathway. The mechanistic and functional principles that underlie the relationship between signalling and endocytosis in cell biology are becoming increasingly evident across many systems.Cells sense the environment and communicate with each other through the ligand-induced activation of signalling receptors at the cell surface. Signalling receptors, similar to other integral plasma membrane proteins, enter the endocytic pathway and are sorted into various endosomal compartments. Endocytosis regulates cell signalling most simply by controlling the number of receptors available for activation in the plasma membrane, and the activation of receptors or downstream effectors often stimulates receptor endocytosis. Studies of receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) have established many examples of this relationship, which functions as a homeostatic regulatory loop to prevent excessive ligand-induced activation of downstream effectors. This paradigm has also been expanded to other receptors, including those for transforming growth factor-β (TGFβ), cytokines, Wnt and Notch. Furthermore, a functionally important relationship between signalling and endocytosis has been convincingly established in worm, fly, zebrafish, frog and mouse models.It is increasingly clear that endocytosis has many effects on signal transduction and, conversely, that receptor signalling regulates the endocytic machinery. This has blurred traditional lines that separate signalling and endocytosis at both the mechanistic and functional levels. Several cellular proteins that function in signalling and endocytosis have also been identified. This limits the degree to which signalling and endocytic machineries can be independently manipulated experimentally, which makes it challenging to precisely elucidate specific relationships between these machineries. There is now a vast collection of published primary literature on this topic, and numerous recent reviews have focused on its various aspects 1,2 . Instead, in this Review we discuss a limited subset of studies that illustrate the major features of the signalling-endocytosis nexus and represent the field more generally. We also attempt

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