Epidermal growth factor pathway substrate 15, Eps15

Eps15 was originally identified as a substrate for the kinase activity of t he epidermal growth factor receptor (EGFR). Eps15 has a tripartite structur e comprising a NH2-terminal portion, which contains three EH domains, a cen tral putative coiled-coil region, and a COOH-terminal domain containing mul tiple copies of the amino acid triplet Aspartate-Proline-Phenylalanine. A p ool of Eps15 is localized at clathrin coated pits where it interacts with t he clathrin assembly complex AP-2 and a novel AP-2 binding protein, Epsin. Perturbation of Eps15 and Epsin function inhibits receptor-mediated endocyt osis of EGF and transferrin, demonstrating that both proteins are component s of the endocytic machinery. Since the family of EH-containing proteins is implicated in various aspects of intracellular sorting, biomolecular strat egies aimed at interfering with these processes can now be envisioned. Thes e strategies have potentially far reaching implications extending to the co ntrol of cell proliferation. In this regard, it is of note that Eps15 has t he potential of transforming NIH-3T3 cells and that the eps15 gene is rearr anged with the HRX/ALL/MLL gene in acute myelogeneous leukemias, thus impli cating this protein in the subversion of cell proliferation in neoplasia. ( C) 1999 Elsevier Science Ltd. All rights reserved.