HETERODIMERIZATION OF THE ERBB-1 AND ERBB-2 RECEPTORS IN HUMAN BREAST-CARCINOMA CELLS - A MECHANISM FOR RECEPTOR TRANSREGULATION
HETERODIMERIZATION OF THE ERBB-1 AND ERBB-2 RECEPTORS IN HUMAN BREAST-CARCINOMA CELLS - A MECHANISM FOR RECEPTOR TRANSREGULATION
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DOI：
10.1021/bi00502a002
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发表时间：
1990-12-18
期刊：
影响因子：
2.9
通讯作者：
YARDEN, Y
中科院分区：
文献类型：
--
作者：
GOLDMAN, R;BENLEVY, R;YARDEN, Y
ErbB-1和erbB-2原癌基因编码同源的膜受体，分别致盲表皮生长因子(EGF)和一个仍未完全表征的配体。已知，EGF与其受体的结合可以增加肿瘤细胞中erbB-2/neu受体的酪氨酸磷酸化。为了探讨这一跨调控途径的机制，我们分析了SKBR-3人乳腺癌细胞中这两种受体之间的相互作用。~(125)I标记的EGF的化学交联表明，标记的EGF受体与erb B-2/neu受体共沉淀。此外，一个360 kdalton分子质量的交联物种也被免疫共沉淀。后者的形成完全依赖于EGF受体的存在，因此似乎代表了erbB-1和erbB-2受体的异源二聚体。体外激酶反应分析表明，EGF结合可诱导受体异源二聚化，并导致二聚化受体的自我磷酸化能力显著增强。此外，对活的SKBR-3细胞的分析表明，大多数EGF诱导的erbB-2/neu受体的反式调节是由于受体的异源二聚化。结论：erbB-1和erbB-2受体的异源二聚体可能为乳腺肿瘤细胞生长因子的双重转导功能提供了机制。
The erbB-1 and erbB-2 protooncogenes encode homologous membrane receptors that respectively blind epidermal growth factor (EGF) and a still incompletely characterized ligand. Binding of EGF to its receptor is known to increase tyrosine phosphorylation of the erbB-2/neu receptor in tumor cells. To investigate the mechanism of this transregulatory pathway, we analyzed the interactions between the two receptors in SKBR-3 human breast carcinoma cells. Chemical cross-linking of 125I-labeled EGF revealed that the radiolabeled EGF receptor coimmunoprecipitates with the erbB-2/neu receptor. In addition a cross-linked species of 360-kdalton molecular mass is also coimmunoprecipitated. The formation of the latter species is absolutely dependent on the presence of EGF receptor and thus appears to represent a heterodimer of the erbB-1 and erbB-2 receptors. In vitro kinase reaction assays revealed that receptor heterodimerization is induced by EGF binding and leads to a dramatic increase in the self-phosphorylation capacity of the dimerized receptors. Moreover, analysis of living SKBR-3 cells suggested that most of the EGF-induced transregulation of the erbB-2/neu receptor is due to receptor heterodimerization. In conclusion, heterodimers of erbB-1 and erbB-2 receptors may provide a mechanism for dual transductory functions of growth factors of breast tumor cells.