Tzahar E, Yarden Y
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Biochim Biophys Acta. 1998 Feb 20;1377(1):M25-37. doi: 10.1016/s0304-419x(97)00032-2.
Extensive clinical and biochemical evidence implicates ErbB-2, a transmembrane tyrosine kinase related to growth factor receptors, in the development, metastasis, and resistance to therapy of multiple, common human carcinomas. Previous attempts to uncover an ErbB-2-specific ligand led to isolation of the neuregulin (NRG) family, but these ligands, like all other growth factors with an EGF-like motif, only indirectly active ErbB-2. On the other hand, biochemical and genetic evidence suggest a non-autonomous function of ErbB-2 in an interactive ErbB signaling network. Accordingly, the oncoprotein acts as a shared signaling subunit of primary growth factor receptors. By stabilizing heterodimers with other ErbB proteins, ErbB-2 prolongs and enhances signal transduction by a large group of stroma-derived growth factors. Furthermore, we have proposed a model in which all ErbB-2 ligands are bivalent and bind to ErbB-2 with low affinity, following high affinity binding to a primary receptor with which ErbB-2 is heterodimerized. Thus the presence of ErbB-2 in relevant ErbB heterodimeric structures on the surfaces of certain epithelial tumor cells can amplify signals arising from the binding of stromal ErbB ligands. This effect, in turn, may promote the growth of carcinoma cells.
大量临床和生化证据表明，与生长因子受体相关的跨膜酪氨酸激酶ErbB-2参与多种常见人类癌症的发生、转移及对治疗的耐药性。以往试图寻找ErbB-2特异性配体的研究导致了神经调节蛋白（NRG）家族的分离，但这些配体与所有其他具有表皮生长因子（EGF）样基序的生长因子一样，只能间接激活ErbB-2。另一方面，生化和遗传学证据表明，ErbB-2在相互作用的ErbB信号网络中具有非自主功能。因此，该癌蛋白作为主要生长因子受体的共享信号亚基。通过与其他ErbB蛋白稳定异二聚体，ErbB-2延长并增强了一大类基质衍生生长因子的信号转导。此外，我们提出了一个模型，其中所有ErbB-2配体都是二价的，在与ErbB-2异二聚化的主要受体高亲和力结合后，以低亲和力与ErbB-2结合。因此，某些上皮肿瘤细胞表面相关ErbB异二聚体结构中存在ErbB-2可以放大基质ErbB配体结合产生的信号。反过来，这种效应可能促进癌细胞的生长。
