Clathrin-mediated Endocytosis Signaling

Different mechanisms are available for the endocytic internalization of a variety of particles (molecules, viruses, bacteria...), including clathrin-mediated endocytosis, caveolar endocytosis, macropinocytosis and non-clathrin, non-caveolae endocytosis. Clathrin-mediated endocytosis is the major pathway for the internalization of nutrients, hormones and other signaling molecules from the plasma membrane into intracellular compartments. Clathrin-mediated endocytosis involves the assembly of clathrin lattices on the cytoplasmic surface of the plasma membrane through the recruitment of the endocytic adaptor complex AP2. The tetrameric adaptor AP2 serves to link clathrin to the membrane by binding to clathrin and PIP2, which is the predominant phosphoinositide of the plasma membrane. Moreover, AP2 recognized the internalization signals located in the cytoplasmic domain of the transmembrane receptors bound to cargo. The formation of clathrin-coated pits (CCP) involves numerous AP2-interacting proteins that can be classified into two groups: 1. the accessory proteins involved in the clathrin-coated vesicle (CCV) formation, such as Eps15, epsin, SNX9, AP180/CALM, AMPH, HIP1/HIP1R, etc.) and 2. the alternative adaptors involved in recognition of specific receptors that do not directly interact with AP2, such as ARH and Dab2 for the recognition of LDLR, numb for the recognition of activated receptor tyrosine kinases (RTK), β-arrestins for the recognition of ligand-activated G protein-coupled receptors (GPCR), etc. Cargos bound to their respective receptors are incorporated into the newly formed CCPs. At this point, Dynamin is recruited rapidly along with cortactin, N-WASP, ARP2/3, actin, Endophilin and Synaptojanin, leading to the release of clathrin-coated vesicle from the plasma membrane, through Dynamin activation and actin polymerization. Following internalization and coat disassembly, the vesicles fuse with early endosomes. From early endosomes, the receptors can recycle back to the plasma membrane, can be transported to nucleus or can be sorted to late endosomes for lysosomal degradation.