Pinkas-Kramarski R, Lenferink A E, Bacus S S, Lyass L, van de Poll M L, Klapper L N, Tzahar E, Sela M, van Zoelen E J, Yarden Y
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
Oncogene. 1998 Mar 12;16(10):1249-58. doi: 10.1038/sj.onc.1201642.
The ErbB-1 receptor tyrosine kinase binds to six different growth factors, whose prototype is the epidermal growth factor (EGF). Two homologous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth factors, the Neu differentiation factors (NDFs/neuregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the three other ErbB proteins. Here we report that at high concentrations, EGF can induce cell growth and differentiation in the absence of ErbB-1. This function is shared by betacellulin, but not by three other ligands, including the transforming growth factor alpha (TGFalpha). The functional receptor was identified as a heterodimer between ErbB-3 and ErbB-2, a previously identified oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In addition, when co-expressed, blocking either receptor by using site-specific antibodies inhibited EGF and betacellulin activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through analysis of chimeras between EGF and TGFalpha, we identified the middle portion of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In conclusion, cooperative and promiscuous binding of stroma-derived growth factors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be significant to cancer development. The mechanistic implications of our results for a model that attributes receptor dimerization to ligand bivalency, as well as to a recently proposed mechanism of secondary dimerization, are discussed.
ErbB-1受体酪氨酸激酶可结合六种不同的生长因子，其原型是表皮生长因子（EGF）。另外两种同源上皮受体ErbB-3和ErbB-4可结合另一类生长因子家族——Neu分化因子（NDFs/神经调节蛋白）的所有亚型。ErbB家族的第四个成员ErbB-2，是其他三种ErbB蛋白的配体占据复合物的首选异二聚体伴侣。在此我们报告，在高浓度下，EGF可在没有ErbB-1的情况下诱导细胞生长和分化。β细胞ulin也具有此功能，但另外三种配体，包括转化生长因子α（TGFα）则没有。功能性受体被鉴定为ErbB-3和ErbB-2之间的异二聚体，这是一种先前已鉴定的致癌复合物。单独表达时，ErbB-3和ErbB-2均不能介导EGF的信号传导。此外，共表达时，使用位点特异性抗体阻断任一受体均可抑制EGF和β细胞ulin的活性，表明ErbB-3和ErbB-2之间存在严格的协同作用。通过对EGF和TGFα之间嵌合体的分析，我们确定EGF的中间部分（环B）是能够激活ErbB-2/ErbB-3的位点。总之，上皮细胞表达的ErbB-2/ErbB-3异二聚体对基质衍生生长因子的协同和混杂结合可能对癌症发展具有重要意义。我们讨论了这些结果对将受体二聚化归因于配体双价性的模型以及最近提出的二级二聚化机制的机制意义。
