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 a recent review, see 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 GNA11 gene encodes the alpha-11 subunit (Gα11). 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; Landis et
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. GNA11. My Cancer
(Updated December 4).
Last Updated: December 4, 2015
GNA11 in Melanoma
Somatic mutations in GNA11 have been
found in up to 34% of primary uveal melanomas and up to 63% of uveal melanoma metastases (Van Raamsdonk et al.
2010). In all malignant melanoma, GNA11 mutations are found in about 1.2% of
GNA11 mutations have not been detected in extraocular melanoma (Van Raamsdonk et al.
The majority of melanoma-associated mutations
in GNA11 have been detected at codon 209 within exon 5 of the gene, a region within the
catalytic (GTPase) domain of GNA11. Mutation at this site inactivates the GTPase
domain, resulting in a constitutively active GNA11 protein which is 'locked' in the GTP bound
form (Kalinec et al.
1992; Landis et al.
1989). Expression of GNA11 Q209L in mice results in melanocyte transformation and
increased signaling through the MAPK pathway (Van Raamsdonk et al.
In the vast majority of cases, GNA11 mutations
are non-overlapping with other oncogenic mutations
found in melanoma (e.g., BRAF mutations, KIT
mutations, etc.). Currently, there are no
direct anti-GNA11 therapies available.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. GNA11 in Melanoma. My
Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/gna11/
(Updated June 18).
Last Updated: June 18, 2015
GNA11 c.546_547delCCinsTT (R183C) Mutation in Melanoma
|Location of mutation
|Frequency of GNA11 mutations
in primary uveal melanoma
||34% (van Raamsdonk
et al. 2010)
|Frequency of R183C mutation in GNA11-mutated
primary uveal melanoma
van Raamsdonk et
|Implications for Targeted Therapeutics
|Response to BRAF inhibitors
||Unknown at this time
|Response to MEK inhibitors
||Unknown at this timea
|Response to KIT inhibitors
||Unknown at this time
The R183C mutation results in an amino acid substitution at position 183 in
GNA11, from an arginine (R) to a cysteine (C). This mutation
occurs within the catalytic (GTPase) domain of GNA11 and results in a constitutively active
GNA11 protein (Kalinec et al.
1992; Landis et al.
1989). GNA11 mutations are usually found in tumors with no driver mutations detected in
NRAS, BRAF, KIT, and other genes. Currently, there are no direct anti-GNA11 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., D. Johnson, J. Sosman. 2015. GNA11
c.546_547delCCinsTT (R183C) Mutation in
Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/gna11/335/
(Updated June 16).
Last Updated: June 16, 2015
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