Elucidation of the mechanism by which receptor tyrosine kinases (RTKs) modulate cellular physiology in response to stimuli is critical to the understanding of growth regulation. Miscues in RTK signaling pathways can result in cellular transformation and ultimately in cancer. Two novel EGF receptor substrates designated EGF-receptor pathway substrates 8 and 15, or Eps8 and Eps15, have been described. Epsin is a 90 kDa binding partner to Eps15. Both epsin and Eps15 have an ubiquitous tissue distribution but are concentrated in presynaptic nerve terminals specialized for the Clathrin-mediated endocytosis of synaptic vesicles. Disruption of epsin function blocks Clathrinmediated endocytosis. Epsin along with its binding partner Eps15 is proposed to be involved in the assistance of Clathrin coat rearrangement during Clathrin coated pit invagination. Epsin 2 and epsin 2a are also associated with Clathrin-mediated endocytosis and are enriched in the brain in the peri-Golgi region.