A Function for EGF-Induced Eps15 Ubiquitination in Endocytosis

Abstract

Binding of growth factors, such as the epidermal growth factor (EGF), to their specific receptors on the cell surface causes the initiation of a signal transduction cascade which leads to changes in gene expression and finally to cell division. Inactivation of the EGF-receptor can occur via several mechanisms, such as receptor mediated transmodulation (Northwood and Davis, 1990), receptor dephosphorylation (Faure et al., 1992) and receptor downregulation (for review see Sorkin and Waters, 1993). The importance of down-regulation as a negative regulatory mechanism of receptor tyrosine kinase signaling is stressed by the observation that defects in this regulation can facilitate cellular transformation (Wells et al., 1990) and tumor formation (Masui et al., 1991). Receptor down-regulation results in the loss of EGF binding sites from the plasma membrane by internalization of the receptors. EGF-receptors enter the cell via receptor mediated endocytosis, a process involving clathrin coated pits and vesicles. The coat is composed of a number of proteins, such as the adaptor proteins (Aps), the heavy and light chain of clathrin, forming the clathrin lattice (for review see Schmid, 1992) and, as recently has been demonstrated, Eps 15 (Tebar et al., 1996; van Delft et al., 1997).