Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions
Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions
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DOI：
10.1002/j.1460-2075.1996.tb00603.x
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发表时间：
1996-05-15
期刊：
影响因子：
11.4
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
PinkasKramarski, R;Soussan, L;Yarden, Y
ErbB家族包括两个受体ErbB-1和ErbB-3，分别与表皮生长因子和Neu分化因子结合，以及一个孤儿受体ErbB-2。与ErbB-1和ErbB-2不同，ErbB-3的固有酪氨酸激酶是催化损伤的。通过使用异位表达这三种ErbB蛋白或它们的组合的白介素3依赖的细胞，我们发现ErbB-3没有任何生物活性，但ErbB-1和ErbB-2都可以重建其极强的促分裂活性。ErbB-3的反式激活与异二聚体的形成有关，并反映在受体的磷酸化和配体亲和力的反调上，受体间的相互作用使分级的增殖和生存信号成为可能：异二聚体比同二聚体更有效，含ErbB-3的复合体，特别是ErbB-2/ErbB-3复合体比ErbB-1复合体更活跃，然而，当两种受体共同表达时，ErbB-1信号对ErbB-3具有优势。尽管所有的受体组合都激活了丝裂原活化蛋白激酶ERK和c-Jun激酶，但它们的内吞速率和与中介信号蛋白的偶联程度不同，可以想象，组合受体的相互作用使信号转导多样化，并在顺式和反式中对激酶缺陷的ErbB-3的优势有丝分裂活性进行双重调节。
The ErbB family includes two receptors, ErbB-1 and ErbB-3, that respectively bind to epidermal growth factor and Neu differentiation factor, and an orphan receptor, ErbB-2. Unlike ErbB-1 and ErbB-2, the intrinsic tyrosine kinase of ErbB-3 is catalytically impaired. By using interleukin-3-dependent cells that ectopically express the three ErbB proteins or their combinations, we found that ErbB-3 is devoid of any biological activity but both ErbB-1 and ErbB-2 can reconstitute its extremely potent mitogenic activity. Transactivation of ErbB-3 correlates with heterodimer formation and is reflected in receptor phosphorylation and the transregulation of ligand affinity, Inter-receptor interactions enable graded proliferative and survival signals: heterodimers are more potent than homodimers, and ErbB-3-containing complexes, especially the ErbB-2/ErbB-3 heterodimer, are more active than ErbB-1 complexes, Nevertheless, ErbB-1 signaling displays dominance over ErbB-3 when the two receptors are coexpressed. Although all receptor combinations activate the mitogen-activated protein kinases ERK and c-Jun kinase, they differ in their rate of endocytosis and in coupling to intervening signaling proteins, It is conceivable that combinatorial receptor interactions diversify signal transduction and confer double regulation, in cis and in trans, of the superior mitogenic activity of the kinase-defective ErbB-3.