MITOGENIC SIGNALLING ERBB/EGFR FAMILY AND ITS ROLE IN NEOPLASIA

点击翻译按钮获取中文摘要

The gene product encoded by a third member of the erbB/epidermal growth factor receptor (EGFR) subfamily, erbB-3, was characterized as a transmembrance glycoprotein, gp180erbB-3 possessing properties characteristic of a receptor-like tyrosine kinase closely related to the EGFR and the erbB-2 protein. Tunicamycin and pulse-chase experiments revealed that the mature protein was processed by N-linked glycosylation of a 145-kDA core polypeptide. the intrinsic catalytic function was shown by its ability to autophosphorylate in vitro. Ligand-dependent signaling by its cytoplasmic domain was established employing transfectants that express a chimeric EGFR/erbB-3 protein. Demonstration of EGF-dependent autophosphorylation of the chimera and induction of growth proliferation in a model system, combined with detection of constitutive tyrosine phosphorylation of gp180erbB-3 in a subset of human mammary tumor cell lines, implicated activation of erbB-3 signaling function in human neoplasia. furthermore, utilizing the chimeric receptor transfectant, it was established that the cytoplasmic erbB-3 signaling pathway differs from that of structurally related family members. In addition, known members of the EGF superfamily did not exhibit triggering activity for gp180erbB-3 recombinantly expressed in NIH/3T3 fibroblasts. Conversely, erbB-3-specific ligand activity was identified by screening conditioned media from normal and tumor cell lines for their ability to trigger erbB-3 tyrosine phosphorylation. In addition, the coding sequences of erbB-2-specific ligands were molecularly cloned for recombinant expression in eukaryotic and prokaryotic host cells in efforts to characterize the role of different erbB/EGFR family members as well as their possible cooperative function in tumorigenesis.