Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
Mol Pharmacol. 2024 Oct 17;106(5):198-215. doi: 10.1124/molpharm.124.000743.
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.
G 蛋白偶联受体（GPCRs）与异三聚体 G 蛋白偶联，异三聚体 G 蛋白由α和γ亚基组成，将细胞外信号转化为细胞内信号通路的激活。通常，GPCR 介导的激活导致 G 蛋白α亚基（G）上 GDP 与 GTP 的交换和 G-GTP 与 G 蛋白βγ亚基（G）的解离，这两者都可以调节各种信号通路。G 结合的 GTP 的水解使蛋白回到 G-GDP 并允许与 G 重新组装形成非活性异三聚体。在保守的谷氨酰胺和精氨酸氨基酸中发现了天然存在的 G 突变，这些突变通过抑制 GTP 水解破坏了典型的 G 蛋白循环，使这些突变体持续激活。有趣的是，由于它们能够维持异常信号而无需 GPCR 激活，这些失调的 G 突变体存在于许多不同的癌症中。本综述将重点介绍在癌症中越来越认识到这种持续激活的 G 突变的普遍性以及激活的信号通路。此外，我们将讨论关于这些持续激活的 G 如何受到调节的新知识，不同的突变在生化上有何不同，以及突变激活的 G 与 GPCR 激活的 G 有何独特之处。最后，我们将讨论直接针对持续激活的 G 突变体开发抑制剂的最新进展。意义陈述：G 蛋白α亚基（G）中的组成性激活突变广泛存在于并有助于许多人类癌症的发展。为了开发抑制这些突变 G 引起的失调致癌信号的方法，了解导致组成性 G 激活的机制以及调节细胞中突变激活的 G 的独特机制至关重要。G 在各种癌症中激活突变的普遍性使 G 蛋白成为开发治疗药物的有吸引力的靶标。
