Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated G in Human Cancer.

G protein-coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of and γ 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 subunits (G) and the dissociation of G-GTP and G protein subunits (G), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by G returns the protein to G-GDP and allows reassociation with G to reform the inactive heterotrimer. Naturally occurring mutations in G 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 G 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 G mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active G are regulated, how different mutations are biochemically distinct, and how mutationally activated G are unique compared with GPCR-activated G Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active G mutants. SIGNIFICANCE STATEMENT: Constitutively activating mutations in G protein subunits (G) widely occur in and contribute to the development of many human cancers. To develop ways to inhibit dysregulated, oncogenic signaling by these mutant G, it is crucial to better understand mechanisms that lead to constitutive G activation and unique mechanisms that regulate mutationally activated G in cells. The prevalence of activating mutations in G in various cancers makes G proteins compelling targets for the development of therapeutics.