Endocytosis and endosomal sorting of receptor tyrosine kinases

Abstract

Activation of receptor tyrosine kinases (RTKs) by their ligands at the cell surface results in acceleration of RTK endocytosis and subsequent targeting of internalized RTKs to lysosomes for degradation. Rapid internalization and efficient sorting of an activated RTK to lysosomes lead to a dramatic reduction in the cellular level of an RTK protein, a phenomenon called ligand-induced RTK downregulation. Endocytic trafficking is the major regulator of RTK signaling, but the mechanisms of activity-dependent RTK endocytosis are not well understood. In this chapter we will describe clathrin-dependent and clathrin-independent pathways of RTK internalization and the intracellular traffic routes of internalized RTKs, as well as membrane compartments and molecular mechanisms involved in endocytosis and endosomal sorting of RTKs. Based on the studies of endocytosis of epidermal growth factor receptor (EGFR) as the prototypic experimental system, common itineraries and mechanisms of endocytic trafficking of RTKs will be highlighted. The deviations from these common trafficking rules observed in studies of other members of the RTK family will also be discussed.