3. Mutational landscape of G proteins and GPCRs in cancer

Besides aberrant expression, mutations are another key factor that cause dysregulation of GPCR signaling. GPCRs are mutated in approximately 20% of all cancers, and recurrent mutations in particular GPCRs are linked to the advancement of cancer (Kan et al. , 2010). Genetic mutations in the coding regions of GPCRs may lead to changes in ligand binding affinity, receptor expression, or the efficiency of G protein coupling, which further affect downstream signaling (Stoy & Gurevich, 2015). In the following section, we will present the mutational landscape of G proteins and GPCRs, with a focus on widespread mutations identified in cancer.

3.1 Widespread mutations in G proteins

G proteins play an instrumental role in regulating cellular signal transduction. Gαs, Gαi, Gαq/11 and Gα12/13 are four main types of Gα subunits. Sequencing has identified many encoding mutations of G proteins, where non-synonymous mutations are highly prevalent over synonymous mutations and mostly affect constitutive activity (CA) of GPCR signaling (O’hayre et al. , 2013). Overall,GNAS (G protein Subunit Alpha S) is mutated in 4.45% of all tumor sequences deposited in the Catalogue of Somatic Mutations in Cancer (COSMIC), making it the most frequently mutated G proteins in human cancer (Table 2) (Forbes et al. , 2017). GNAS mutations are commonly linked to endocrine-related tumors, including certain types of pancreatic and thyroid cancers, pituitary adenomas and others. Most of the well-known GNAS mutations are clustered around two hotspot residues, R201 and Q227, leading to sustained activation of the Gα subunit and downstream signaling pathways (Turan & Bastepe, 2015). This sustained signaling can promote cell proliferation and inhibit apoptosis, contributing to tumor initiation and progression.GNAQ (G Protein Subunit Alpha Q) mutations are notably associated with uveal melanoma, a rare but aggressive form of eye cancer. In uveal melanoma, activating mutations in the hotspot residues Q209, and R183 lead to persistent activation of the MAPK pathway, driving uncontrolled cell growth (Onken et al. , 2008). Unlike many other cancers, these GNAQ mutations are prevalent and are often early events in uveal melanoma, making them attractive targets for precision medicine.GNA11 (G Protein Subunit Alpha 11) is closely related toGNAQ , and mutations in GNA11 are also implicated in uveal melanoma, highlighting the redundancy and shared pathways of these G proteins in certain cancers (Piaggio et al. , 2022).Table 2 Mutational landscape of G proteins in cancer. Table was adapted from O’Hayre et al. (O’hayre et al., 2013).