NOVEL HER2 SECRETED PROTEIN THAT BINDS TO P185HER2

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DESCRIPTION: (adapted verbatim from the investigator's abstract) Overexpression of p185HER-2/neu receptor tyrosine kinase (RTK), but not other members of the human EGF receptor family, is sufficient to confer a transformed phenotype and is associated with more aggressive clinical outcome in breast cancer and possibly other human cancers. Because of the clinical importance of controlling the activation of p185HER-2, intensive efforts have been directed toward the identification of a specific ligand, although to date no specific, high affinity ligand has been identified. The potent oncogenic activity of p185HER-2 may be due to an uncharacterized ligand, or to the exceptional capacity of p185HER-2 to dimerize, which is required for RTK activation. We have identified a novel secreted product of the HER-2 gene encoded by an alternative transcript that is expressed in normal human tissues. The protein product, p68ECDIIIa, is composed of subdomains I and II from p185 and a novel C-terminus designated ECDIIIa. Further experiments show that p68ECDIIIa specifically binds to p185HER-2 at the cell surface, but may not stimulate tyrosine phosphorylation. Moreover, carcinoma cells that overexpress p185HER-2 appear to have a mechanism for repression of p68ECDIIIa expression. Our hypothesis is that the unique ECDIIIa domain mediates specific binding to p185HER-2 and the resulting interaction with p68ECDIIIa prevents p185HER-2 dimerization and subsequent signal transduction. We now propose to determine the mechanism of the interaction of p68 with p185 by determining their binding affinities and by defining the domains and subdomains required for their interaction. The functional significance of p68ECDIIIa to p185HER-2 homomeric and heteromeric signal transduction will be examined by the effects of recombinant p68ECDIIIa on dimerization, growth factor binding affinity to heteromeric receptors, receptor autophosphorylation, and mitogenic signal transduction. We will use heterologous p68ECDIIIa expression to test the hypothesis that p68 inhibits tumor cell growth providing a selective pressure for tumor cells which overexpress p185. Studies on the structural and function of a p185HER-2 binding protein, encoded by the HER-2 gene itself, may provide novel insight for understanding the role of HER-2 in normal development and in human cancers.