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 have been described, designated EGF-receptor pathway substrates 8 and 15, or Eps8 and Eps15. Epsin is a 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 Clathrin-mediated 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 2a, and 2b are splicing variants of epsin 2, which is associated with Clathrin-mediated endocytosis and are enriched in the brain in the peri-Golgi region.