This review article describes the pathways and mechanisms of endocytosis and post-endocytic sorting of the EGF receptor (EGFR/ErbB1) and other members of the ErbB family. Growth factor binding to EGFR accelerates its internalization through clathrin-coated pits which is followed by the efficient lysosomal targeting of internalized receptors and results in receptor down-regulation. The role of EGFR interaction with the Grb2 adaptor protein and Cbl ubiquitin ligase, and receptor ubiquitination in the clathrin-dependent internalization and sorting of EGFR in multivesicular endosomes is discussed. Activation and phosphorylation of ErbB2, ErbB3 and ErbB4 also results in their ubiquitination. However, these ErbBs are internalized and targeted to lysosomes less efficiently than EGFR. When overexpressed endocytosis-impaired ErbBs may inhibit the internalization and degradation of EGFR.

Endocytosis is the major regulator of signaling from receptor tyrosine kinases (RTKs). The canonical model of RTK endocytosis involves rapid internalization of an RTK activated by ligand binding at the cell surface and subsequent sorting of internalized ligand-RTK complexes to lysosomes for degradation. Activation of the intrinsic tyrosine kinase activity of RTKs results in autophosphorylation, which is mechanistically coupled to the recruitment of adaptor proteins and conjugation of ubiquitin to RTKs. Ubiquitination serves to mediate interactions of RTKs with sorting machineries both at the cell surface and on endosomes. The pathways and kinetics of RTK endocytic trafficking, molecular mechanisms underlying sorting processes, and examples of deviations from the standard trafficking itinerary in the RTK family are discussed in this work.F unctional activities of transmembrane proteins, including the large family of RTKs, are controlled by intracellular trafficking. RTKs are synthesized in the endoplasmic reticulum, transported to Golgi apparatus, and then delivered to the plasma membrane. At the cell surface RTKs undergo constitutive endocytosis (internalization) at a rate similar to that of other integral membrane proteins. Constitutive internalization of RTKs is much slower than their constitutive recycling from endosomes back to the cell surface. Therefore, RTKs are accumulated at the cell surface, which allows maximal accessibility to extracellular ligands. The rates of the constitutive internalization, recycling, and degradation determine the half-life of an RTK protein, which varies depending on the nature of the RTK and the cell type, and typically positively correlates with the expression level of the RTK. For example, the turnover rates range from t 1/2 ,

Four independent mechanisms for uptake of activated EGFR are identified by a combination of receptor mutagenesis and RNA interference approaches.