A PROTEIN-BINDING DOMAIN, EH, IDENTIFIED IN THE RECEPTOR TYROSINE KINASE SUBSTRATE EPS15 AND CONSERVED IN EVOLUTION

In this report we structurally and functionally define a binding domai n that is involved in protein association and that we have designated EH (for Eps15 homology domain). This domain was identified in the tyro sine kinase substrate Eps15 on the basis of regional conservation with several heterogeneous proteins of yeast and nematode. The EH domain s pans about 70 amino acids and shows approximate to 60% overall amino a cid conservation, We demonstrated the ability of the EH domain to spec ifically bind cytosolic proteins in normal and malignant cells of mese nchymal, epithelial, and hematopoietic origin. These observations prom pted our search for additional EH-containing proteins in mammalian cel ls. Using an EH domain-specific probe derived from the eps15 cDNA, we cloned and characterized a cDNA encoding an EH-containing protein with overall similarity to Eps15; we designated this protein Eps15r (for E ps15-related), Structural comparison of Eps15 and Eps15r defines a fam ily of signal transducers possessing extensive networking abilities in cluding EH-mediated binding and association with Src homology 3-contai ning proteins.