Gq-coupled GPCRs mediate the oncogenic activity of Gαq-Q209L/P mutants in uveal melanoma cells.
Aumiller Jenna L JL, Luo Jiansong J, Komolov Konstantin E KE, Sosa Julie M JM et al.
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 Gαq and Gα11 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 Gq-coupled GPCRs, including 5-hydroxytryptamine receptor 2B (HTR2B), enhanced the oncogenic signaling of Gαq-QL. Although HTR2B antagonists alone had little to no inhibitory effects, they enhanced the sensitivity of UM cells to the Gαq-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 Gαq-QL/QP mutants into an inactive conformation to a greater extent than did YM-254890 alone. Our study demonstrates that Gq-coupled GPCRs enhance the oncogenicity of mutationally active Gαq proteins and that antagonism of HTR2B promotes an inactive state of Gαq-QL/QP that increases sensitivity to an inhibitor of Gαq.