The role of ubiquitylation in receptor endocytosis and endosomal sorting

Ligand-induced activation of transmembrane receptors activates intracellular signaling cascades that control vital cellular processes, such as cell proliferation, differentiation, migration and survival. Receptor signaling is modulated by several mechanisms to ensure that the correct biological outcome is achieved. One such mechanism, which negatively regulates receptor signaling, involves the modification of receptors with ubiquitin. This post-translational modification can promote receptor endocytosis and targets receptors for lysosomal degradation, thereby ensuring termination of receptor signaling. In this Commentary, we review the roles of ubiquitylation in receptor endocytosis and degradative endosomal sorting by drawing on the epidermal growth factor receptor (EGFR) as a well-studied example. Furthermore, we elaborate on the molecular basis of ubiquitin recognition along the endocytic pathway through compartment-specific ubiquitin-binding proteins and highlight how endocytic sorting machineries control these processes. In addition, we discuss the importance of ubiquitin-dependent receptor endocytosis for the maintenance of cellular homeostasis and in the prevention of diseases such as cancer. This article is part of a Minifocus on Ubiquitin. For further reading, please see related articles: 'Ubiquitin and SUMO in DNA repair at a glance' by Helle D. Ulrich (J. Cell Sci. 125, 249-254). 'Emerging regulatory mechanisms in ubiquitin-dependent cell cycle control' by Annamaria Mocciaro and Michael Rape (J. Cell Sci. 125, 255-263). 'Cellular functions of the DUBs' by Michael J. Clague et al. (J. Cell Sci. 125, 277-286). 'HECT and RING finger families of E3 ubiquitin ligases at a glance' by Meredith B. Metzger et al. (J. Cell Sci. 125, 531-537). 'Non-canonical ubiquitin-based signals for proteasomal degradation' by Yelena Kravtsova-Ivantsiv and Aaron Ciechanover (J. Cell Sci. 125, 539-548). 'No one can whistle a symphony alone how different ubiquitin linkages cooperate to orchestrate NF-kappa B activity' by Anna C. Schmukle and Henning Walczak (J. Cell Sci. 125, 549-559).