MITOGENIC SIGNALLING ERBB/EGFR FAMILY AND ITS ROLE IN NEOPLASIA

由erbB/表皮生长因子第三成员编码的基因产物 因子受体（EGFR）亚家族，erbB-3，被表征为 跨膜糖蛋白，gp 180 erbB-3，具有 受体样酪氨酸激酶的特征与 EGFR和erbB-2蛋白。 衣霉素和脉冲追踪实验 结果表明，成熟蛋白是通过N-连接糖基化进行加工的 145-kDA核心多肽。 内在的催化功能是 通过其在体外自磷酸化的能力来证明。 配体依赖性 通过其胞质结构域的信号传导建立， 表达嵌合EGFR/erbB-3蛋白的转染子。 示范 嵌合体的EGF依赖性自身磷酸化和 模型系统中的生长增殖，结合检测 人胃癌细胞中gp 180 erbB-3的组成性酪氨酸磷酸化 乳腺肿瘤细胞系，涉及erbB-3信号转导的激活 在人类肿瘤形成中的作用 此外，利用嵌合体， 受体转染子，确定细胞质erbB-3 信号通路不同于结构上相关的家族 成员 EGF超家族的成员没有 对重组表达的gp 180 erbB-3显示触发活性， NIH/3 T3成纤维细胞。 相反，erbB-3特异性配体活性是 通过筛选正常细胞和肿瘤细胞的条件培养基进行鉴定 细胞系中，它们具有触发erbB-3酪氨酸磷酸化的能力。 在 此外，erbB-2特异性配体的编码序列被克隆。 分子克隆用于真核重组表达， 原核宿主细胞在努力表征不同的作用， erbB/EGFR家族成员及其可能的协同功能 在肿瘤发生中。

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.