Jcb_201705017 1..10

1 The Rockefeller University Press J. Cell Biol. https://doi.org/10.1083/jcb.201705017 Introduction The plasma membrane (PM) serves as a physical barrier that separates the cytosolic milieu of the cell from the comparatively harsh external chemical environment. It also serves as a sophisticated communication platform through which cells receive and respond to messages from each other, as well as sense and respond to changes in their environment. Cell surface signaling receptors, such as receptor tyrosine kinases (RTKs), G protein–coupled receptors (GPCRs), and cytokine receptors, are activated by binding to their ligands (e.g., growth hormones, peptide agonists, and cytokines). Activated receptors then transmit messages across the PM by initiating signaling cascades in the cytosol that alter cell physiology and/or behavior. The uptake of macromolecules across the PM, a process called endocytosis, occurs via multiple pathways, all involving the inward budding of vesicles that carry cargo (e.g., receptors and their bound ligands, membrane transporters, and adhesion molecules) into the cell (Conner and Schmid, 2003). Although endocytosis is a mechanism well known to terminate receptor signaling (Grandal and Madshus, 2008), it has also become clear that endocytosis is required for the initiation of some signaling cascades (Platta and Stenmark, 2011). Moreover, both the endocytic pathway taken by surface receptors and their intracellular fate can quantitatively and qualitatively affect the activity of downstream signaling pathways and thereby control cellular responses (Di Fiore and De Camilli, 2001; Sorkin and von Zastrow, 2009; Platta and Stenmark, 2011; Di Fiore and von Zastrow, 2014). Thus, endocytosis regulates signaling. Several studies, described in this review, provide compelling evidence that signaling downstream of surface receptors can, in turn, regulate endocytosis and alter the intracellular itinerary of activated receptors (Puthenveedu and von Zastrow, 2006; Reis et al., 2015, 2017). The cross talk between signaling and endocytosis has implications for cancer progression, as alterations in survival, proliferative, and migratory signals are essential for metastasis. Indeed, several reviews have described how endocytosis can be “dysregulated” or “derailed” in cancer cells (Lanzetti and Di Fiore, 2008; Mosesson et al., 2008; Mellman and Yarden, 2013). These descriptors, which connote “defective” endocytosis, are supported by lists of cancer-associated mutations, translocations, or altered expression levels among components of the endocytic machinery. Recent findings, however, suggest that by taking advantage of the reciprocal cross talk between signaling and endocytosis, cancer cells elaborate mechanisms to enhance endocytosis and recycling, potentially in receptor-selective manners. Therefore, rather than defective, I propose the more deliberate term “adaptive endocytosis,” whereby evolving cancer cells specifically adopt mechanisms that quantitatively and/or qualitatively alter endocytic trafficking to enhance their survival, proliferative, and migratory properties. As described below, this perspective opens new avenues of investigation into the regulation of endocytic trafficking in both normal and cancer cells.