A soluble form of the receptor tyrosine kinase encoded by the avian proto-oncogene c-erbB1 is composed of only the ligand-binding domain of the receptor, and has been demonstrated to have dramatic, c-erbB1- dependent, growth inhibitory potential in vitro (Flickinger et al., 1992 MCB 12:883-893). No studies have been performed to date, however, to determine the mechanism by which soluble ErbB1 (ErbB1-S) inhibits native receptor function. I have recently cloned the cDNA encoding the soluble form of the human c-erb product. In this application, we propose to use this cDNA clone to test the hypothesis that the mechanism by which ErbB1- S receptors modulate c-erbB1-dependent growth inhibition is via direct interaction with the native receptor. I propose to characterize and express the soluble form of the human c-erbB1 gene, and to use chemical cross-linking studies to test the ability of this protein to directly interact with, and thereby inhibit both native receptor homodimerization and tyrosine kinase activity. In addition, I propose to test the ability of ErbB1-S to interfere with the heterodimerization of the full-length ErbB1 and ErbB2 receptors. Since transformation by wild type ErbB2 requires synergistic interaction with ErbB1, ErbB1-S may also be capable of blocking ErbB2-mediated transformation, and this hypothesis will tested directly. The clear role of the c-erbB proto-oncogene family in modulating cell growth and transformation has generated intense interest in elucidating the mechanisms by which the activities of this receptor family are regulated. The successful completion of these studies will contribute to our understanding of the mechanisms by which this family of receptors becomes activated and mediates the process of oncogenesis.