MITOGENIC SIGNALLING ERBB/EGFR FAMILY AND ITS ROLE IN NEOPLASIA

ErbB-3蛋白发挥的配体依赖的信号转导功能 此前被发现在人类肿瘤中被激活。使用嵌合体 表皮生长因子受体(EGFR)/ErbB-3受体转基因。它 表明这一功能需要激活细胞质信号 不同于其他家庭成员的道路。尤其是。ErbB-3- 介导的有丝分裂信号涉及PI 3-的有效募集 激活酶活性。而它缺乏明显的磷脂酶活性 C(PLC)--γ或GTP酶激活蛋白(GAP)。在寻找一种自然的 莱兰德。对条件培养液和纯化的蛋白质进行诱导试验 乳腺上皮细胞中ErbB-3特异性酪氨酸磷酸化的研究 高水平表达ErbB-3蛋白的NIH/3T3细胞。 利用这种方法，证明了细菌表达的EGF Hereglin的结构域能够触发ErbB-3酪氨酸磷酸化 在体内以及相关的受体上。ErbB-4。当以高位表达时 在NIH/3T3成纤维细胞中的表达。更有甚者。净化和 一种显示ErbB-3触发的肝素结合蛋白的显微测序 活性研究表明，这种蛋白质不同于 赫里古林家族。使用简并的寡核苷酸，特定的DNA 通过基于聚合酶链式反应(PCR)的方法产生探针 并分离出cDNA3个克隆。完整的结构和功能 这个假定的ErbB-3配体的特征尚待确定。终于来了。 有证据表明，几个ErbB的生物合作 模型系统中包括ErbB-2和ErbB-3的家庭成员为 在人类肿瘤中是平行的。

A ligand-dependent signaling function exerted by the ErbB-3 protein has previously been found activated in human neoplasia. Employing a chimeric epidermal growth factor receptor (EGFR)/ErbB-3 receptor transfectant. it was shown that this function entails activation of cytoplasmic signaling pathways distinct from other family members. In particular. ErbB-3- mediated mitogenic signaling involved efficient recruitment of PI 3- kinase activity. while it lacked significant activation of phospholipase C (PLC)-gamma or GTPase activating protein (GAP). In search of a natural ligand. conditioned media and purified proteins were tested for induction of ErbB-3-specific tyrosine phosphorylation in mammary epithelial cells and NIH/3T3 transfectants expressing the ErbB-3 protein at high levels. Using this approach, it was shown that the bacterially expressed EGF domain of heregulin was able to trigger ErbB-3 tyrosine phosphorylation in vivo as well as of a related receptor. ErbB-4. when expressed at high levels in NIH/3T3 fibroblasts. Moreover. purification and microsequencing of a heparin-binding protein exhibiting ErbB-3 triggering activity has established that this protein was distinct from members of the heregulin family. Using degenerate oligonucleotides, specific DNA probes were generated by a polymerase chain reaction (PCR)-based approach and cDNA clones were isolated. The complete structural and functional characterization of this putative ErbB-3 ligand is pending. Finally. evidence was established that biological cooperation of several ErbB family members including ErbB-2 and ErbB-3 in a model system is paralleled in human tumors.