Endocytosis of Receptor Tyrosine Kinases

Growth factors and their respective receptor tyrosine kinases (RTKs) play pivotal roles in normal cellular functions, such as proliferation and motility, as well as in pathogenesis, including cancer. The amplitude and kinetics of growth factor signaling are determined mainly by a highly regulated endocytic process, which sorts activated receptors to degradation in lysosomes. Molecular mechanisms underlying receptor down-regulation are being unraveled: the active receptor recruits Cbl ubiquitin ligases that decorate it with multiple monomers of ubiquitin. In parallel, Nedd4/AIP4 ubiquitin ligases attach ubiquitin to a set of ubiquitin-binding adaptors (e.g., Epsin and the EGF-receptor protein substrate, Eps15) necessary for the assembly of a clathrin coat. Analogous but distinct ubiquitin-binding platforms underlie receptor sorting into shuttling vesicles at the plasma membrane, early endosomes and a prelysosomal compartment called the multi-vesicular body. In addition to ubiquitylation, phopshorylation of both RTKs and coat adaptors orchestrate receptor sorting in concert with machineries responsible for membrane bending and vesicle fusion. The default route diverts internalized receptors back to the plasma membrane, thus enabling prolonged signaling associated with pathological processes. This review concentrates on the epidermal growth factor receptor (EGFR) as a prototype and highlights the major events occurring on its journey to the lysosome.