Clathrin/AP-2-dependent endocytosis: a novel playground for the pharmacological toolbox?

Endocytosis is a vital process for mammalian cells by which they communicate with their environment, internalize nutrients, hormones, or growth factors, or take up extracellular fluids and particles. The best studied among the various pathways to ingest material from the extracellular side is clathrin/AP-2-mediated endocytosis. The past several years have allowed us to gain unprecedented molecular insights into the role of the heterotetrameric AP-2 adaptor complex as a central protein-protein and protein-lipid interaction hub at the plasmalemma. During the initial stages of clathrin-coated pit formation, AP-2 interacts with phosphoinositides and cargo membrane proteins as well as with a variety of accessory proteins and clathrin to coordinate clathrin coat polymerization with membrane deformation and cargo recruitment. In addition, a growing list of alternative adaptors provides opportunity for clathrin-dependent cargo selective pathways of internalization and endosomal sorting. Many of these interactions are now understood in structural detail and are thus amenable to pharmacological interference. In this review we will summarize our present state of knowledge about AP-2 and its partners in endocytosis and delineate potential strategies for pharmacological manipulations.