LIGAND DEPENDENT SIGNALING BY ERBB-4

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Three different isoforms of the heregulin ligands which have been expressed in bacteria and purified were cloned and molecularly characterized; they are the source for the biological studies that were conducted on NIH/3T3 and 32D systems. These cells have been transfected with erbB-2, erbB-3 and erbB-4 proto-oncogenes to elucidate the role that the HRG ligands may have on binding, triggering, biological and biochemical activation of those tyrosine kinase receptors. The ergB-4 proto-oncogene was cloned and molecularly characterized. and a chimeric receptor epidermal growth factor (EGF)/erbB-4 with the extracellular domain of the epidermal growth factor receptor (EGFR) and the intracellular domains of the erbB-4 tyrosine kinase was genetically engineered in order to perform studies on the biochemical cascade pathway of activation of erbB-4 upon EGF triggering with particular regard to PI 3-kinase PLC-A. GTPase activating protein (GAP) and Shc recruitment. Furthermore. based upon close structural similarity and frequent coexpression of erbB-2 and erbB-3 in normal cells and human tumors of epithelial origin, a study is in progress to denote the possible cooperative function of these receptors in signaling pathways.