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

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. [Display omitted] ► Human cancers harbor frequent mutations in Gq-linked GPCRs and Gαq subunits ► A genome-wide RNAi screen revealed that Trio is essential for activating AP-1 via Gαq ► A network of Trio-regulated Rho GTPases and MAPKs links Gq to the nucleus ► A hard-wired Gq-Trio signaling axis promotes the growth of many human malignancies