Proteomic and functional genomic landscape of receptor tyrosine kinase and ras to extracellular signal-regulated kinase signaling.
Proteomic and functional genomic landscape of receptor tyrosine kinase and ras to extracellular signal-regulated kinase signaling.
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DOI：
10.1126/scisignal.2002029
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发表时间：
2011-10-25
影响因子：
7.3
通讯作者：
Perrimon N
中科院分区：
文献类型：
--
作者：
Friedman AA;Tucker G;Singh R;Yan D;Vinayagam A;Hu Y;Binari R;Hong P;Sun X;Porto M;Pacifico S;Murali T;Finley RL Jr;Asara JM;Berger B;Perrimon N
表征信号网络的程度和逻辑对于理解诸如细胞命运决定和肿瘤发生和化疗抗性机制等生理和病理生理背景中的特异性至关重要。基于细胞的RNA干扰（RNAi）筛选能够推断大量调节信号通路的基因，但这些筛选无法直接提供网络结构。我们描述了一个整合的网络周围的典型受体酪氨酸激酶（RTK）-Ras-细胞外信号调节激酶（ERK）信号通路，通过结合并行的全基因组RNAi屏幕与蛋白质-蛋白质相互作用（PPI）映射串联亲和纯化-质谱。我们发现，在所有测试条件下，PPI或RNAi筛选命中总数中只有一小部分被分离，并且其中大部分代表已知的经典途径组分，这表明大部分核心经典ERK途径是已知的。由于大多数新发现的调节剂可能是细胞类型和RTK特异性的，我们的分析提供了一个资源，以了解如何通过这种临床相关的途径输出在不同的情况下进行调节。我们报告了几个以前未知的调节剂，包括CG 10289和PpV，果蝇直系同源的丝氨酸/苏氨酸蛋白磷酸酶6复合物的两个组件;果蝇直系同源的TepIV，一个glycophosphatidylinositol连接蛋白在人类癌症中突变; CG 6453，葡萄糖苷酶II的非催化亚基;和Rtf 1，组蛋白甲基转移酶。
Characterizing the extent and logic of signaling networks is essential to understanding specificity in such physiological and pathophysiological contexts as cell fate decisions and mechanisms of oncogenesis and resistance to chemotherapy. Cell-based RNA interference (RNAi) screens enable the inference of large numbers of genes that regulate signaling pathways, but these screens cannot provide network structure directly. We describe an integrated network around the canonical receptor tyrosine kinase (RTK)–Ras–extracellular signal–regulated kinase (ERK) signaling pathway, generated by combining parallel genome-wide RNAi screens with protein-protein interaction (PPI) mapping by tandem affinity purification–mass spectrometry. We found that only a small fraction of the total number of PPI or RNAi screen hits was isolated under all conditions tested and that most of these represented the known canonical pathway components, suggesting that much of the core canonical ERK pathway is known. Because most of the newly identified regulators are likely cell type– and RTK-specific, our analysis provides a resource for understanding how output through this clinically relevant pathway is regulated in different contexts. We report in vivo roles for several of the previously unknown regulators, including CG10289 and PpV, the Drosophila orthologs of two components of the serine/threonine–protein phosphatase 6 complex; the Drosophila ortholog of TepIV, a glycophosphatidylinositol-linked protein mutated in human cancers; CG6453, a noncatalytic subunit of glucosidase II; and Rtf1, a histone methyltransferase.
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影响因子：
7.3
作者：
Evangelista, Marie;Lim, Tze Yang;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
64.8
作者：
Gavin, AC;Aloy, P;Superti-Furga, G
通讯作者：
Superti-Furga, G
影响因子：
14.9
作者：
Chien, S;Reiter, LT;Gribskov, M
通讯作者：
Gribskov, M
影响因子：
14.9
作者：
Ceol A;Chatr Aryamontri A;Licata L;Peluso D;Briganti L;Perfetto L;Castagnoli L;Cesareni G
通讯作者：
Cesareni G
影响因子：
64.5
作者：
Ashton-Beaucage, Dariel;Udell, Christian M.;Therrien, Marc
通讯作者：
Therrien, Marc