Guanine nucleotide binding proteins (G
proteins) are a family of heterotrimeric
proteins which couple seven transmembrane
domain receptors to intracellular
cascades, including neurotransmitter, growth factor, and hormone signaling pathways (for review, see Neves, Ram, and
Iyengar 2002 and Rosenbaum, Rasmussen, and
Kobilka 2009). Heterotrimeric G proteins are composed of three subunits, Gα,
Gß, and Gγ (Figure 1); each of the subunits has many different family members.
The GNAQ gene encodes the Gq alpha subunit (Gαg). Receptor activation catalyzes the
exchange of GDP (guanosine diphosphate) to GTP (guanosine triphosphate) on the Gα
subunit, resulting in the dissociation of the Gα subunit from Gßγ. Both Gα
and Gßγ can then activate downstream cellular signaling pathways. The signal is
terminated when GTP is hydrolyzed to GDP by the intrinsic GTPase activity of the Gα
subunit. Oncogenic mutations result in a loss of this intrinsic GTPase activity, resulting
in a constitutively active Gα subunit (Kalinec et al. 1992;
Figure 1. Schematic of
heterotrimeric G protein signaling.
Activation of a 7 transmembrane G-protein coupled receptor
results in exchange of GDP for GTP on the Gα subunit. The GTP bound form of Gα
then dissociates from Gßγ. Multiple downstream cellular effector pathways can be
activated by G protein signaling.
Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. GNAQ. My Cancer
(Updated December 4).
Last Updated: December 4, 2015
GNAQ in Melanoma
Somatic mutations in GNAQ have been
found in ~50% of primary uveal melanomas and up to 28% of uveal melanoma metastases (Onken et al. 2008;
Van Raamsdonk et al.
Raamsdonk et al. 2010). In all malignant melanoma, GNAQ mutations are
found in about 1.3% of samples (COSMIC).
GNAQ mutations are rare in extraocular melanoma (Van Raamsdonk et al.
The majority of melanoma-associated mutations
in GNAQ have been detected at codon 209 within exon 5 of the gene, a region within the
catalytic (GTPase) domain of GNAQ. Mutation at this site inactivates the GTPase domain,
resulting in a constitutively active GNAQ protein, which is 'locked' in the GTP bound form (Kalinec et al.
1992; Landis et al.
1989). Expression of GNAQ Q209L in mice results in melanocyte transformation and
increased signaling through the MAPK pathway (Van Raamsdonk et al.
In the vast majority of cases, GNAQ mutations
are non-overlapping with other oncogenic mutations
found in melanoma (e.g., BRAF mutations, KIT
mutations, etc.). Currently, there are no
direct anti-GNAQ therapies available.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. GNAQ in Melanoma. My
Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/gnaq/
(Updated June 18).
Last Updated: June 18, 2015
GNAQ c.626A>T (Q209L) Mutation in Melanoma
The Q209L mutation results in an amino acid substitution at position 209 in GNAQ,
from a glutamine (Q) to a leucine (L). This mutation
occurs within the catalytic (GTPase) domain of GNAQ and results in a constitutively active GNAQ
protein (Kalinec et al.
1992; Landis et al.
1989). GNAQ mutations are usually found in tumors with no driver mutations detected in
NRAS, BRAF, KIT, and other genes. Currently, there are no direct anti-GNAQ therapies available.
a In a phase II trial, no significant difference in efficacy was reported in
a subset of uveal melanoma patients whose tumors harbored GNAQ or GNA11 Exon 5
mutations treated with the MEK1/2 inhibitor
selumetinib compared with chemotherapy (Carvajal et al. 2014).
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. GNAQ c.626A>T (Q209L)
Mutation in Melanoma. My Cancer
(Updated June 16).
Last Updated: June 16, 2015
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