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Endothelin signaling promotes melanoma tumorigenesis driven by constitutively active GNAQ
Author(s) -
Jain Fagun,
Longakit Anne,
Huang Jenny LiYing,
Van Raamsdonk Catherine D.
Publication year - 2020
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12900
Subject(s) - heterotrimeric g protein , gnaq , biology , carcinogenesis , melanocyte , microbiology and biotechnology , g protein coupled receptor , gtpase activating protein , melanoma , gq alpha subunit , g protein , cancer research , receptor , signal transduction , genetics , mutation , gene
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 Gα 1 . Constitutively active, oncogenic versions of Gα q and Gα 11 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 Gα 11 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.