TRIO Mediates G Protein–Coupled Receptor Mitogenic Signaling

Mitogens that signal through G protein–coupled receptors (GPCR) primarily activate the Gq subtype of heterotrimeric G proteins. The identification of activating mutations in genes encoding 2 Gq subunits, GNAQ and GNA11, in approximately 80% of uveal melanomas and mutations in Gq-coupled GPCRs (Gq-GPCR) in other cancers suggests that Gq-PCR-mediated mitogenic signaling plays a role in tumorigenesis but the relevant signal transduction mechanisms remain uncharacterized. To identify the signaling networks that link Gq-GPCRs to cell proliferation, Vaqué and colleagues performed a genome-wide RNA interference screen in Drosophila S2 cells for genes required for activation of the AP-1 transcription factor, a key outcome of mitogenic Gq-GPCR signaling. Among the most significant hits were Rho family GTPases and their direct downstream targets, but only one Rho-specific guanine nucleotide exchange factor (GEF), Trio, was identified as a potential link between Gq-GPCRs and Rho GTPase. TRIO was required for activation of RAC1 and RHOA and mitogenic signaling in mammalian cells following synthetic Gq-GPCR stimulation and bound activated Gq proteins at the plasma membrane, providing evidence that Gq-GPCRs can signal through TRIO directly without a requirement for canonical second messenger-based systems. Of note, TRIO mRNA is elevated in a variety of human cancers, and the TRIO locus at chromosome 5p15.2 is commonly amplified in cervical and head and neck cancers. TRIO knockdown dramatically reduced DNA synthesis and xenograft tumor growth of cervical and head and neck cancer cells and significantly decreased the mitogenic signaling, proliferation, and tumorigenicity of primary GNAQ-mutant uveal melanoma cells. Together, these findings establish TRIO as a key player in Gq-GPCR mitogenic signal transduction and suggest that small molecules targeting Gq–TRIO interactions or TRIO GEF activity may be effective in cancers with Gqs or Gq-GPCRs mutations or TRIO amplification.

Vaqué JP, Dorsam RT, Feng X, Iglesias-Bartolome R, Forsthoefel DJ, Chen Q, et al. A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors. Mol Cell 2012 Nov 21 [Epub ahead of print].