Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Pigment Cell Melanoma Res. 2013 May;26(3):408-14. doi: 10.1111/pcmr.12089. Epub 2013 Apr 2.
We recently identified neuregulin-1 (NRG1) as a novel target of Notch1 required in Notch-dependent melanoma growth. ERBB3 and ERBB4, tyrosine kinase receptors specifically activated by NRG1, have been shown to be either elevated in melanoma cell lines and tumors or to be mutated in 20% of melanomas, respectively. While these data support key roles of NRG1 and its receptors in the pathogenesis of melanoma, whether ERBB3 and ERBB4 display redundant or exclusive functions is not known. Here, we show that ERBB3 and ERBB4 inhibition results in distinct outcomes. ERBB3 inhibition ablates the cellular responses to NRG1, results in AKT inactivation and leads to cell growth arrest and apoptotic cell death. In contrast, ERBB4 knockdown mildly affects cell growth, has no effects on cell survival and, importantly, does not alter the responses to NRG1. Finally, we identified ERBB2 as a key coreceptor in NRG1-dependent ERBB3 signaling. ERBB2 forms a complex with ERBB3, and its inhibition recapitulates the phenotypes observed upon ERBB3 ablation. We propose that an NRG1-ERBB3-ERBB2 signaling unit operates in melanoma cells where it promotes growth and survival.
我们最近发现神经调节蛋白 1（NRG1）是 Notch1 的一个新靶点，在 Notch 依赖性黑色素瘤生长中是必需的。表皮生长因子受体（ERBB）3 和 ERBB4 是酪氨酸激酶受体，其被 NRG1 特异性激活，已经显示在黑色素瘤细胞系和肿瘤中升高，或者在 20%的黑色素瘤中发生突变。虽然这些数据支持 NRG1 和其受体在黑色素瘤发病机制中的关键作用，但 ERBB3 和 ERBB4 是否显示冗余或独特的功能尚不清楚。在这里，我们表明 ERBB3 和 ERBB4 的抑制作用会产生不同的结果。ERBB3 的抑制作用会消除细胞对 NRG1 的反应，导致 AKT 失活，并导致细胞生长停滞和细胞凋亡。相比之下，ERBB4 的敲低对细胞生长有轻微影响，对细胞存活没有影响，而且重要的是，不会改变对 NRG1 的反应。最后，我们鉴定出 ERBB2 是 NRG1 依赖性 ERBB3 信号中的关键核心受体。ERBB2 与 ERBB3 形成复合物，其抑制作用再现了 ERBB3 缺失时观察到的表型。我们提出，NRG1-ERBB3-ERBB2 信号单元在黑色素瘤细胞中起作用，促进生长和存活。
