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A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling

机译：功能性RNAi筛选受体酪氨酸激酶和ERK信号调节剂

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Receptor tyrosine kinase (RTK) signalling through extracellular-signal-regulated kinases ( ERKs) has pivotal roles during metazoan development, underlying processes as diverse as fate determination, differentiation, proliferation, survival, migration and growth. Abnormal RTK/ERK signalling has been extensively documented to contribute to developmental disorders and disease, most notably in oncogenic transformation by mutant RTKs(1) or downstream pathway components such as Ras and Raf(2). Although the core RTK/ERK signalling cassette has been characterized by decades of research using mammalian cell culture and forward genetic screens in model organisms, signal propagation through this pathway is probably regulated by a larger network of moderate, context-specific proteins. The genes encoding these proteins may not have been discovered through traditional screens owing, in particular, to the requirement for visible phenotypes. To obtain a global view of RTK/ERK signalling, we performed an unbiased, RNA interference (RNAi), genome-wide, high-throughput screen in Drosophila cells using a novel, quantitative, cellular assay monitoring ERK activation. Here we show that ERK pathway output integrates a wide array of conserved cellular processes. Further analysis of selected components - in multiple cell types with different RTK ligands and oncogenic stimuli - validates and classifies 331 pathway regulators. The relevance of these genes is highlighted by our isolation of a Ste20-like kinase and a PPM-family phosphatase that seem to regulate RTK/ERK signalling in vivo and in mammalian cells. Novel regulators that modulate specific pathway outputs may be selective targets for drug discovery.
机译：通过细胞外信号调节激酶（ERK）传递的酪氨酸激酶（RTK）受体在后生动物发育过程中起着举足轻重的作用，其基本过程如命运决定，分化，增殖，存活，迁移和生长。大量的RTK / ERK信号转导已被广泛报道为导致发育障碍和疾病的原因，最明显的是突变RTKs（1）或下游途径成分如Ras和Raf（2）致癌。尽管核心的RTK / ERK信号盒已经通过使用哺乳动物细胞培养和模型生物中的正向遗传筛选进行了数十年的研究，但通过该途径传播的信号可能受到较大的中度背景特定蛋白网络的调节。尤其是由于需要可见表型，可能无法通过传统的筛选方法发现编码这些蛋白质的基因。为了获得RTK / ERK信号的全局视图，我们使用新颖的，定量的，细胞学监测ERK激活的果蝇细胞进行了无偏倚的RNA干扰（RNAi），全基因组，高通量筛选。在这里，我们显示ERK途径输出整合了一系列保守的细胞过程。对选定成分的进一步分析-在具有不同RTK配体和致癌刺激物的多种细胞类型中-对331种通路调节剂进行了验证和分类。我们分离出的Ste20样激酶和PPM家族磷酸酶似乎在体内和哺乳动物细胞中调节RTK / ERK信号，从而突显了这些基因的相关性。调节特定途径输出的新型调节剂可能是药物发现的选择性目标。

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