G q -coupled GPCRs mediate the oncogenic activity of Gα q -Q209L/P mutants in uveal melanoma cells

G protein–coupled receptors (GPCRs) stimulate heterotrimeric G proteins (Gαβγ) to facilitate downstream signaling, termination of which relies on a glutamine (Q) residue at position 209 in G protein α subunits. In uveal melanoma (UM), the most common intraocular malignancy in adults, >90% of patients harbor Q209L (QL) or Q209P (QP) mutations in Gα q and Gα 11 proteins. Although mutationally active Gα subunits are thought to signal independently of GPCRs, some constitutively active Gα subunits may retain the ability to bind to GPCRs. Here, we demonstrated that G q -coupled GPCRs, including 5-hydroxytryptamine receptor 2B (HTR2B), enhanced the oncogenic signaling of Gα q -QL. Although HTR2B antagonists alone had little to no inhibitory effects, they enhanced the sensitivity of UM cells to the Gα q -specific inhibitor YM-254890, as measured by signaling, cell viability, and proliferation assays. Last, treatment of UM cells with HTR2B antagonists and low concentrations of YM-254890 shifted endogenous Gα q -QL/QP mutants into an inactive conformation to a greater extent than did YM-254890 alone. Our study demonstrates that G q -coupled GPCRs enhance the oncogenicity of mutationally active Gα q proteins and that antagonism of HTR2B promotes an inactive state of Gα q -QL/QP that increases sensitivity to an inhibitor of Gα q .