A Genome-wide RNAi Screen Reveals a Trio-Regulated Rho GTPase Circuitry Transducing Mitogenic Signals Initiated by G Protein-Coupled Receptors

Vaque Jose P.; Dorsam Robert T.; Feng Xiaodong; Iglesias-Bartolome Ramiro; Forsthoefel David J.; Chen Qianming; Debant Anne; Seeger Mark A.; Ksander Bruce R.; Teramoto Hidemi; Gutkind J. Silvio

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A Genome-wide RNAi Screen Reveals a Trio-Regulated Rho GTPase Circuitry Transducing Mitogenic Signals Initiated by G Protein-Coupled Receptors

机译：基因组RNAi筛网显示了由G蛋白偶联受体引发的引发促动信号的三级rNAi筛网

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Activating mutations in GNAQ and GNA11, encoding members of the G alpha(q) family of G protein alpha subunits, are the driver oncogenes in uveal melanoma, and mutations in Gq-linked G protein-coupled receptors have been identified recently in numerous human malignancies. How G alpha(q) and its coupled receptors transduce mitogenic signals is still unclear because of the complexity of signaling events perturbed upon Gq activation. Using a synthetic-biology approach and a genome-wide RNAi screen, we found that a highly conserved guanine nucleotide exchange factor, Trio, is essential for activating Rhoand Rac-regulated signaling pathways acting on JNK and p38, and thereby transducing proliferative signals from G alpha(q) to the nucleus independently of phospholipase C-beta. Indeed, whereas many biological responses elicited by Gq depend on the transient activation of second-messenger systems, Gq utilizes a hard-wired protein-protein-interaction-based signaling circuitry to achieve the sustained stimulation of proliferative pathways, thereby controlling normal and aberrant cell growth.

机译：在GNAQ和GNA11中激活突变，编码Gα（Q）家族的G蛋白α亚基的成员，是UVEAL黑色素瘤的驾驶员诱导物，并且最近在众多人类恶性肿瘤中鉴定了GQ连接的G蛋白偶联受体中的突变。由于在GQ激活时，Gα（Q）及其偶联的受体转导促动信号仍不清楚的信号传导事件的复杂性。使用合成生物学方法和基因组宽的RNAi筛网，我们发现一种高度保守的鸟嘌呤核苷酸交换因子，三重组对于激活作用于JNK和P38的RHOANS RAC调节的信号通路是必不可少的，从而转换来自G的增殖信号α（Q）与磷脂酶C-β的核。实际上，而GQ引发的许多生物反应取决于第二信使系统的瞬态激活，GQ利用基于硬化的蛋白质 - 蛋白质相互作用的信号电路，以实现增殖途径的持续刺激，从而控制正常和异常的细胞生长。

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《Molecular cell》 |2013年第1期|共15页
作者
Vaque Jose P.; Dorsam Robert T.; Feng Xiaodong; Iglesias-Bartolome Ramiro; Forsthoefel David J.; Chen Qianming; Debant Anne; Seeger Mark A.; Ksander Bruce R.; Teramoto Hidemi; Gutkind J. Silvio;
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作者单位

Natl Inst Dent &

Craniofacial Res Oral &

Pharyngeal Canc Branch NIH Bethesda MD 20892 USA;

Ctr Drug Evaluat &

Res Food &

Drug Adm Silver Spring MD 20993 USA;

Natl Inst Dent &

Craniofacial Res Oral &

Pharyngeal Canc Branch NIH Bethesda MD 20892 USA;

Natl Inst Dent &

Craniofacial Res Oral &

Pharyngeal Canc Branch NIH Bethesda MD 20892 USA;

Ohio State Univ Dept Mol Genet Columbus OH 43210 USA;

Sichuan Univ State Key Lab Oral Dis Chengdu 610041 Sichuan Peoples R China;

Univ Montpellier I CNRS Ctr Rech Biochim Macromol UMR 5237 F-34293 Montpellier 5 France;

Ohio State Univ Dept Mol Genet Columbus OH 43210 USA;

Harvard Univ Sch Med Schepens Eye Res Inst Boston MA 02114 USA;

Kojin Hosp Nagoya Aichi 4638530 Japan;

Natl Inst Dent &

Craniofacial Res Oral &

Pharyngeal Canc Branch NIH Bethesda MD 20892 USA;

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正文语种 eng
中图分类细胞生物学;
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1. A Genome-wide RNAi Screen Reveals a Trio-Regulated Rho GTPase Circuitry Transducing Mitogenic Signals Initiated by G Protein-Coupled Receptors [J] . Vaque Jose P., Dorsam Robert T., Feng Xiaodong, Molecular cell . 2013,第1期

机译：基因组RNAi筛网显示了由G蛋白偶联受体引发的引发促动信号的三级rNAi筛网
2. Rho Family GTPases Are Required for Activation of Jak/STAT Signaling by G Protein-Coupled Receptors [J] . Stéphane Pelletier, Fran?ois Duhamel, Philippe Coulombe, Molecular and Cellular Biology . 2003,第4期

机译：Rho家族GTP酶是G蛋白偶联受体激活Jak / STAT信号所必需的
3. Sequence analysis reveals how G protein-coupled receptors transduce the signal to the G protein. [J] . Oliveira L, Paiva PB, Paiva AC, Proteins: Structure, Function, and Genetics . 2003,第4期

机译：序列分析揭示了G蛋白偶联受体如何将信号转导至G蛋白。
4. Genome-wide screens reveal that reduced TOR signaling extends chronological and replicative life span in Saccharomyces cerevisiae [D] . Powers, Ralph Wilson 2006

机译：全基因组筛选显示减少的TOR信号传导延长了酿酒酵母的时间和复制寿命
5. A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing GPCR-initiated mitogenic signals [O] . Jose P. Vaqué, Robert T. Dorsam, Xiaodong Feng, -1

机译：基因组RNAi筛网揭示了一种转换GPCR引发的促动信号的三重量rNOGPTP酶电路
6. Hippo-Independent Activation of YAP by the GNAQ Uveal Melanoma Oncogene through a Trio-Regulated Rho GTPase Signaling Circuitry [O] . Feng Xiaodong, Degese Maria Sol, Iglesias-Bartolome Ramiro, 2014

机译：通过三重调控的Rho GTPase信号传导电路，由GNAQ葡萄膜黑色素瘤癌基因对河马的YAP的独立激活。

A Genome-wide RNAi Screen Reveals a Trio-Regulated Rho GTPase Circuitry Transducing Mitogenic Signals Initiated by G Protein-Coupled Receptors

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