2013
DOI: 10.1016/j.molcel.2012.10.018
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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

Abstract: Activating mutations in GNAQ and GNA11, encoding members of the Gαq family of G protein α subunits, are the driver uveal melanoma oncogenes, while mutations in Gq-linked G proteincoupled receptors (GPCRs) have been identified recently in numerous human malignancies. How Gαq and its coupled receptors transduce mitogenic signals is still unclear, due to the complexity of signaling events perturbed upon Gq activation. Using of a synthetic biology approach and a genome-wide RNAi screen, we found that a highly cons… Show more

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Cited by 139 publications
(162 citation statements)
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References 47 publications
(82 reference statements)
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“…Moreover, the crystal structure of activated G q/11 and p63RhoGEF has been solved, demonstrating that direct binding of activated G q/11 to p63RhoGEF could specifically induce Rho signalling independently of and in competition to PLCb activation (Lutz et al, 2005). Intriguingly, a recent study that utilised a genome-wide RNAi screen in Drosophila cells to identify regulators of AP-1 transcription factor complex activation (downstream of G q ) found that TRIO activation is a requirement for mitogenic signalling mediated by G q , and is part of a 'hard-wired' protein-protein-interaction based signalling circuitry that is required for sustained cellular growth signalling and a regulator of normal and aberrant cellular growth (Vaqué et al, 2013). Together with our data, these studies provide robust evidence that TRIO mediates GPCR activation of downstream transcriptional events, in part by EGFR transactivation.…”
Section: Discussionmentioning
confidence: 99%
“…Moreover, the crystal structure of activated G q/11 and p63RhoGEF has been solved, demonstrating that direct binding of activated G q/11 to p63RhoGEF could specifically induce Rho signalling independently of and in competition to PLCb activation (Lutz et al, 2005). Intriguingly, a recent study that utilised a genome-wide RNAi screen in Drosophila cells to identify regulators of AP-1 transcription factor complex activation (downstream of G q ) found that TRIO activation is a requirement for mitogenic signalling mediated by G q , and is part of a 'hard-wired' protein-protein-interaction based signalling circuitry that is required for sustained cellular growth signalling and a regulator of normal and aberrant cellular growth (Vaqué et al, 2013). Together with our data, these studies provide robust evidence that TRIO mediates GPCR activation of downstream transcriptional events, in part by EGFR transactivation.…”
Section: Discussionmentioning
confidence: 99%
“…Together, the A 2A and A 2B adenosine receptors stimulate G s /G olf -dependent adenylyl cyclase-driven cAMP accumulation, enabling signal transduction to target genes. A 2B adenosine receptors are also coupled to G q proteins, which can activate JNK and p38 via phospholipase C-dependent or -independent pathways ( 9 ). Positioning of adenosine receptors, particularly A 2A and A 2B adenosine receptors that promote an anti-infl ammatory response, on immune cells reduces tissue injury in conditions of cellular stress, enabling maintenance of tissue homeostasis.…”
Section: Adenosine-abundant Tumor Microenvironmentmentioning
confidence: 99%
“…Trio is essential for activating Rho- and Rac-regulated signaling pathways acting on JNK and p38, thereby transducing proliferative signals from Gα(q) to the nucleus independently of phospholipase C-β [47]. These findings might open new avenues for treatment of uveal melanoma.…”
Section: Introductionmentioning
confidence: 99%