Endothelin signaling promotes melanoma tumorigenesis driven by constitutively active GNAQ

• Published in: Pigment cell and melanoma research 2020-11, Vol.33 (6), p.834-849
• Main Authors: Jain, Fagun, Longakit, Anne, Huang, Jenny Li‐Ying, Van Raamsdonk, Catherine D.
• Format: Article
• Language: English
• Subjects: EDNRB; EDNRB gene; endothelin; Endothelins; GNAQ; Melanocytes; Melanoma; Phospholipase; Phospholipase C; Proteins; Receptors; Tumorigenesis; uveal melanoma
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/pcmr.12900

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 Gαq and Gα1. Constitutively active, oncogenic versions of Gαq 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 GNAQQ209L expression in melanocytes in combination with Ednrb gene knockout. The resulting pathological analysis revealed that every aspect of melanomagenesis driven by GNAQQ209L was inhibited. We conclude that even in the presence of oncogenic Gαq, the Ednrb receptor activates normal Gαq and Gα11 proteins. This likely promotes tumorigenesis by activating phospholipase C‐beta, the immediate effector of Gαq/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.