Neu differentiation factor neuregulin isoforms activate distinct receptor combinations
Neu differentiation factor neuregulin isoforms activate distinct receptor combinations
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DOI：
10.1074/jbc.271.32.19029
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发表时间：
1996-08-09
影响因子：
4.8
通讯作者：
Yarden, Y
中科院分区：
文献类型：
--
作者：
PinkasKramarski, R;Shelly, M;Yarden, Y
Neu 分化因子（NDF/神经调节蛋白）的多种异构体可诱导异构体特异性和细胞类型依赖性的多效性细胞反应。通过比较两种主要同工型 α 和 β，揭示了这种异质性的分子基础。两组均与催化受损的受体酪氨酸激酶 ErbB-3 结合，NDF 对其促有丝分裂刺激需要其他 ErbB 蛋白（ErbB-1 或 ErbB-2）的反式激活。通过在白细胞介素 S 依赖性骨髓细胞中表达每对受体，我们发现两种亚型在共表达 ErbB-3 和 ErbB-2 组合的细胞中诱导有丝分裂信号。然而，只有β同工型刺激同时表达ErbB-3和ErbB-1的细胞，并且两种同工型对单独表达ErbB-3的细胞都没有活性。两种亚型均与所有表达 ErbB-3 的细胞结合，尽管亲和力不同，但共刺激促有丝分裂效应与每个辅助受体转磷酸化 ErbB-3 的能力相关。这些结果表明 NDF 同工型在诱导受体异二聚体的能力上有所不同；虽然两种类型的异构体都通过 ErbB-3/ErbB-2 异二聚体发出信号，但只有 β 异构体能够稳定 ErbB-3/ErbB-1 异二聚体。
The multiple isoforms of Neu differentiation factor (NDF/neuregulin) induce a pleiotropic cellular response that is isoform-specific and cell type-dependent. The molecular basis of this heterogeneity was addressed by comparing the two major groups of isoforms, alpha and beta. Both groups bind to the catalytically impaired receptor tyrosine kinase ErbB-3, whose mitogenic stimulation by NDF requires transactivation by other ErbB proteins, either ErbB-1 or ErbB-2. By expressing each pair of receptors in interleukin S-dependent myeloid cells, we found that both isoforms induced mitogenic signals in cells co-expressing the combination of ErbB-3 with ErbB-2. However, only the beta isoform stimulated cells that expressed both ErbB-3 and ErbB-1, and neither isoform was active on cells expressing ErbB-3 alone. Both isoforms bind to all ErbB-3-expressing cells, albeit with different affinities, but the co-stimulatory mitogenic effect is correlated with the ability of each auxiliary receptor to transphosphorylate ErbB-3. These results imply that NDF isoforms differ in their ability to induce receptor heterodimers; whereas both types of isoforms signal through ErbB-3/ErbB-2 heterodimers, only beta isoforms are able to stabilize ErbB-3/ErbB-1 heterodimers.