G_q-coupled GPCRs mediate the oncogenic activity of Gα_q-Q209L/P mutants in uveal melanoma cells.

Authors

Jenna L Aumiller, Jiansong Luo, Konstantin E Komolov, Julie M Sosa, Philip B Wedegaertner

Published in

Science signaling. Volume 19. Issue 963. Pages eaeg1191. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

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 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 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.

PMID:
43008099
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.