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).