Chausovsky A, Tsarfaty I, Kam Z, Yarden Y, Geiger B, Bershadsky A D
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Mol Biol Cell. 1998 Nov;9(11):3195-209. doi: 10.1091/mbc.9.11.3195.
Neuregulin, or neu differentiation factor, induces cell proliferation or differentiation through interaction with members of the ErbB family of receptor tyrosine kinases. We report that neuregulin can also induce profound morphogenic responses in cultured epithelial cells of different origins. These effects include scattering of small epithelial islands and rearrangement of larger cell islands into ordered ring-shaped arrays with internal lumens. The ring-forming cells are interconnected by cadherin- and beta-catenin-containing adherens junctions. In confluent cultures, neuregulin treatment induces formation of circular lumenlike gaps in the monolayer. Both cell scattering and ring formation are accompanied by a marked increase in cell motility that is independent of hepatocyte growth factor/scatter factor and its receptor (c-Met). Affinity-labeling experiments implied that a combination of ErbB-2 with ErbB-3 mediates the morphogenic signal of neuregulin in gastric cells. Indeed, a similar morphogenic effect could be reconstituted in nonresponsive cells by coexpression of ErbB-2 and -3. We conclude that a heterodimer between the kinase-defective neuregulin receptor, ErbB-3, and the coreceptor, ErbB-2, mediates the morphogenetic action of neuregulin.
神经调节蛋白，即神经分化因子，通过与受体酪氨酸激酶的ErbB家族成员相互作用来诱导细胞增殖或分化。我们报告称，神经调节蛋白还能在不同来源的培养上皮细胞中诱导显著的形态发生反应。这些效应包括小上皮岛的分散以及较大细胞岛重排为具有内部管腔的有序环形阵列。形成环的细胞通过含钙黏着蛋白和β-连环蛋白的黏附连接相互连接。在汇合培养物中，神经调节蛋白处理可诱导单层细胞中形成圆形的类似管腔的间隙。细胞分散和环形成均伴随着细胞运动性的显著增加，这与肝细胞生长因子/分散因子及其受体（c-Met）无关。亲和标记实验表明，ErbB-2与ErbB-3的组合介导了神经调节蛋白在胃细胞中的形态发生信号。实际上，通过共表达ErbB-2和-3，可在无反应的细胞中重建类似的形态发生效应。我们得出结论，激酶缺陷型神经调节蛋白受体ErbB-3与共受体ErbB-2之间的异二聚体介导了神经调节蛋白的形态发生作用。
