Abstract
G protein–coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of α and βγ subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein α subunits (Gα) and the dissociation of Gα-GTP and G protein βγ subunits (Gβγ), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by Gα returns the protein to Gα-GDP and allows reassociation with Gβγ to reform the inactive heterotrimer. Naturally occurring mutations in Gα have been found at conserved glutamine and arginine amino acids that disrupt the canonical G protein cycle by inhibiting GTP hydrolysis, rendering these mutants constitutively active. Interestingly, these dysregulated Gα mutants are found in many different cancers due to their ability to sustain aberrant signaling without a need for activation by GPCRs. This review will highlight an increased recognition of the prevalence of such constitutively activating Gα mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active Gα are regulated, how different mutations are biochemically distinct, and how mutationally activated Gα are unique compared with GPCR-activated Gα. Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active Gα mutants.
SIGNIFICANCE STATEMENT Constitutively activating mutations in G protein α subunits (Gα) widely occur in and contribute to the development of many human cancers. To develop ways to inhibit dysregulated, oncogenic signaling by these mutant Gα, it is crucial to better understand mechanisms that lead to constitutive Gα activation and unique mechanisms that regulate mutationally activated Gα in cells. The prevalence of activating mutations in Gα in various cancers makes Gα proteins compelling targets for the development of therapeutics.
Footnotes
- Received August 1, 2024.
- Accepted August 21, 2024.
This study was supported by National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM138943] (to P.B.W.) and [Grant T32 GM144302] (to J.L.A.) and Department of Defense [Grants ME200047 and ME220054] (to P.B.W.).
No author has an actual or perceived conflict of interest with the contents of this article.
↵1M.B.D. and J.L.A. contributed equally to this work as first authors.
- Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics
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