[PDF][PDF] A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors

JP Vaqué, RT Dorsam, X Feng, R Iglesias-Bartolome… - Molecular cell, 2013 - cell.com
JP Vaqué, RT Dorsam, X Feng, R Iglesias-Bartolome, DJ Forsthoefel, Q Chen, A Debant…
Molecular cell, 2013cell.com
Activating mutations in GNAQ and GNA11, encoding members of the Gα q family of G
protein α 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 Gα 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 …
Summary
Activating mutations in GNAQ and GNA11, encoding members of the Gαq family of G protein α 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 Gαq 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 Rho- and Rac-regulated signaling pathways acting on JNK and p38, and thereby transducing proliferative signals from Gαq to the nucleus independently of phospholipase C-β. 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.
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