Endothelin signaling promotes melanoma tumorigenesis driven by constitutively active GNAQ

The G-protein-coupled receptor, endothelin receptor B (EDNRB), is an important regulator of melanocyte survival and proliferation. It acts by stimulating downstream heterotrimeric G proteins, such as Gα_q and Gα₁ . Constitutively active, oncogenic versions of Gα_q and Gα₁₁ drive melanomagenesis, but the role of Ednrb in the context of these mutant G proteins has not been previously examined. In this paper, we used a knock-in mouse allele at the Rosa26 locus to force oncogenic GNAQ^Q209L expression in melanocytes in combination with Ednrb gene knockout. The resulting pathological analysis revealed that every aspect of melanomagenesis driven by GNAQ^Q209L was inhibited. We conclude that even in the presence of oncogenic Gα_q , the Ednrb receptor activates normal Gα_q and Gα₁₁ proteins. This likely promotes tumorigenesis by activating phospholipase C-beta, the immediate effector of Gα_q/11 . These findings suggest that it might be possible to target upstream receptors to offset the effects of hyperactive G proteins, recognized as the cause of a growing number of human disorders.