MITOGENIC SIGNALLING ERBB/EGFR FAMILY AND ITS ROLE IN NEOPLASIA

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We have recently isolated a third member of the erbB/EGF receptor subfamily and designated it as erbB-3. Based upon structural and biochemical features of a transmembrane tyrosine kinase closely related to the EGFR and erbB-2 proteins, we investigated whether the erbB-3 protein functions as a growth factor receptor. In the absence of a specific erbB-3 ligand we engineered a chimeric receptor containing the extracellular domain of the EGFR and the cytoplasmic domain of the erbB-3 protein. Following transfection of NIH/3T3 cells with the expression vector and marker selection, we could demonstrate that the erbB-3 signalling function is ligand responsive as indicated by EGF-dependent tyrosine phosphorylation and mitogenicity of the chimeric receptor. In addition, the observation of high erbB-3 phosphotyrosine levels in certain human breast tumor cell lines suggested constitutive activation of the erbB-3 signalling function in human neoplasia. Measuring erbB-3 tyrosine phosphorylation in vivo, we have identified conditioned medium from cells lines with putative erbB-3 specific ligand activity. Ongoing studies focus on the protein purification of this activity for the functional and molecular characterization of an erbB-3 specific ligand. Furthermore, cytoplasmic signalling pathways important in erbB-3 signal transduction are investigated employing the chimeric EGFR/erbB-3 transfectants.