GNA11 (guanine nucleotide binding protein (G protein), alpha 11 (Gq class))

2011-03-01 Klaus G Griewank , Swapna Vemula , Boris C Bastian Affiliation

Department of Pathology, Human Oncology, Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA (KGG, BCB); Department of Pathology, University of California, San Francisco, CA, USA (SV)

Identity

HGNC

GNA11

LOCATION

19p13.3

LOCUSID

2767

ALIAS

FBH,FBH2,FHH2,GNA-11,HHC2,HYPOC2

FUSION GENES

Show Gene Fusions

DNA/RNA

Numbers pertain to amount of nucleotides in exons and introns of human GNA11. Untranscribed sequences are yellow, transcribed ones are blue. The arrows refer to the start and stop codon.

Description

The GNA11 gene is composed of 7 exons spanning a region of 27044 bp.

Transcription

The transcribed mRNA has ORF is 1080 nucleotides.

Pseudogene

Processed pseudogene GNA11 is on chromosome 7, 65970152 to 65971210.

Proteins

The diagram shows the general functional domains of G alpha 11 in respect to the amino acid residues and the corresponding exons. The alpha helical domain is found in all G alpha family members. Switch regions (SR), the areas that change their conformation based on if GTP or GDP is bound, are shown in orange (SR1: 182-192, SR2: 204-224, SR3: 236-247). The location of the 183 and 209 mutations are shown and affect switch regions 1 and 2 respectively. The GTPase domain is both essential for hydrolyzing bound GTP as well as binding downstream effectors. Adapted from Mizuno and Itoh, 2009.

Description

Aminoacids: 359. Molecular weight: 42123 daltons.
GNA11 is a proto-oncogene that belongs to the Gq family of the G alpha family of G protein coupled receptors. It is highly homologous to GNAQ.

Expression

GNA11 is generally expressed ubiquitously, an exception being platelets, where only GNAQ is expressed.

Localisation

Cytoplasmic. Signaling occurs at the membrane, which requires N-terminal lipid modification (palmitoylation) of the protein.

Function

GNA11 is a G protein alpha unit associating with a beta and a gamma subunit. Upon ligand binding to G protein coupled receptors, GNA11 binds GTP, which leads to activation and disassociation from the beta and gamma subunits. Known downstream signaling partners are phospholipase C (PLC) beta and RhoA. PLC beta upon activation releases inositol triphosphate (IP3) and diacylglycerol (DAG) from membrane phosphatidylinositol-3-phosphate. RhoA activation is mediated through proteins such as p63 RhoGef, Duet and Trio by GNAQ, and may thus also be mediating Rho activation by GNA11. GNA11 activation has been shown to induce MAP Kinase activation, possibly via DAG-mediated activation of protein kinase C isoforms. Many other proteins shown to bind GNAQ and or GNA11 have been reported, many with regulatory functions, thus named GRK (G Protein regulatory kinases) or RGS (regulator of G protein signaling) proteins.

Homology

GNA11 is part of the G q family of alpha proteins. This family consists of GNAQ, GNA11, GNA14 and GNA15. On an aminoacid level GNA11 is 90% homologous to GNAQ, 82% homologous to GNA14 and 55% homologous to GNA15.

Mutations

Note

The mutations that have been described in melanocytic neoplasia have previously been demonstrated to inhibit the GTPase function and lead to decreased (R183) or completely (Q209) abolished ability to hydrolyze GTP to GDP, locking the protein in the GTP bound, constitutively active state. Experimental in vitro and in vivo data has shown that fitting with the degree of GTPase inhibition Q209 mutations are more potent activators than R183 mutations.

Germinal

No known germinal mutations.

Somatic

Q209 mutations have been described in uveal melanomas (32% primary, 57% metastasis) and blue nevi (6.5%).
R183 mutations have only been described in uveal melanoma (2% primary, 6% metastasis). Overall frequencies and distribution of GNA11 mutations as compared to GNAQ in uveal and cutaneous melanocytic tumors are listed in the table below.

Categories	n°	GNA11	GNAQ	Either
Blue Nevi	139	7%	56%	63%
Uveal melanoma, primary	163	34%	48%	82%
Uveal melanoma, metastasis	23	62%	28%	90%
Uveal nevus	1	0%	100%	100%
Conjunctival melanoma	9	0%	0%	0%
Other nevi	105	0%	0%	0%
Extra-ocular melanomas	273	0%	1%	1%
Total	713

In the table, frequencies of mutations in GNAQ and GNA11 found in different melanocytic proliferations are listed.

Implicated in

Entity name

Blue nevi (6.5%)

Note

The mutations of GNA11 or its paralog GNAQ are expected to be early events in oncogenesis. A mutation in either gene alone is often found in benign proliferations of dermal melanocytes such as blue nevi. Segmental dermal melanocytic hyperplasia of the first trigeminal branch are called Nevi of Ota. In Caucasians Nevus of Ota is a risk factor for uveal melanoma. Similar segmental lesions in the shoulder area are termed Nevus of Ito. These proliferations of dermal melanocytes and blue nevi are benign, but can evolve into melanoma at a low frequency.

Prognosis

Blue nevi as well as segmental melanocytoses are typically harmless, with only a low probability of progressing to melanoma.

Entity name

Uveal melanoma

Note

Primary uveal Melanoma (34%), Uveal melanoma metastases (62%).
Uveal melanoma is an aggressive form of eye cancer. It represents the most common eye cancer and has an incidence of about 2-8 people per million in Caucasians. It can originate in the ciliary body, the iris or most commonly the choroid.

Prognosis

Uveal melanoma is an aggressive cancer with a 10 year survival rate of approximately 50%. The primary tumor is often only recognized at a stage where it has already metastasized. Metastasis in uveal melanoma occurs predominantly to the liver. The prognosis of uveal melanomas is highly dependent on the presence of additional genetic alterations, loss of chromosome 3 in particular.

Cytogenetics

A frequent chromosomal aberration associated with poor prognosis is the loss of chromosome 3. A gene on this chromosome called BAP1, found to be mutated over 80% of metastasizing uveal melanomas, was recently identified.

Entity name

Other entities

Note

Activating mutations of GNA11 have not been found in other malignancies although a recent publication screened a panel of 922 different tumor samples.
There is a reporting of reduced mRNA and protein levels of GNA11 in breast cancer. This indicates expression levels of GNA11 may be relevant in some settings.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
12759536	2003	Reduced expression of GNA11 and silencing of MCT1 in human breast cancers.	Asada K et al
8550609	1996	Functional importance of the amino terminus of Gq alpha.	Hepler JR et al
16182515	2006	Cell signalling diversity of the Gqalpha family of heterotrimeric G proteins.	Hubbard KB et al
16365560	2006	Metastatic uveal melanoma.	Kivelä T et al
19936769	2010	Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.	Küsters-Vandevelde HV et al
19718445	2009	Mutational profile of GNAQQ209 in human tumors.	Lamba S et al
18096806	2007	Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs.	Lutz S et al
19212139	2009	Functions and regulatory mechanisms of Gq-signaling pathways.	Mizuno N et al
19369209	2009	Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.	Orth JH et al
8622452	1996	Prognostic implications of monosomy 3 in uveal melanoma.	Prescher G et al
15763193	2005	Uveal melanoma: epidemiologic aspects.	Singh AD et al
15339913	2004	A novel Galphaq/11-selective inhibitor.	Takasaki J et al
21083380	2010	Mutations in GNA11 in uveal melanoma.	Van Raamsdonk CD et al
20966218	2010	Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complex.	Waldo GL et al
1946421	1991	Characterization of G-protein alpha subunits in the Gq class: expression in murine tissues and in stromal and hematopoietic cell lines.	Wilkie TM et al

Other Information

Locus ID:

NCBI: 2767
MIM: 139313
HGNC: 4379
Ensembl: ENSG00000088256

Variants:

dbSNP: 2767
ClinVar: 2767
TCGA: ENSG00000088256
COSMIC: GNA11

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000088256	ENST00000078429	P29992
ENSG00000088256	ENST00000587636	K7EL62
ENSG00000088256	ENST00000588401	A0A087WVZ3

Expression (GTEx)

100

150

200

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Calcium signaling pathway	KEGG	ko04020
Gap junction	KEGG	ko04540
Long-term depression	KEGG	ko04730
GnRH signaling pathway	KEGG	ko04912
Calcium signaling pathway	KEGG	hsa04020
Gap junction	KEGG	hsa04540
Long-term depression	KEGG	hsa04730
GnRH signaling pathway	KEGG	hsa04912
Pathways in cancer	KEGG	hsa05200
Vascular smooth muscle contraction	KEGG	hsa04270
Vascular smooth muscle contraction	KEGG	ko04270
Chagas disease (American trypanosomiasis)	KEGG	ko05142
Chagas disease (American trypanosomiasis)	KEGG	hsa05142
Amoebiasis	KEGG	ko05146
Amoebiasis	KEGG	hsa05146
Cholinergic synapse	KEGG	hsa04725
Insulin secretion	KEGG	hsa04911
cGMP-PKG signaling pathway	KEGG	hsa04022
cGMP-PKG signaling pathway	KEGG	ko04022
Hemostasis	REACTOME	R-HSA-109582
Platelet activation, signaling and aggregation	REACTOME	R-HSA-76002
Signal amplification	REACTOME	R-HSA-392518
ADP signalling through P2Y purinoceptor 1	REACTOME	R-HSA-418592
Thromboxane signalling through TP receptor	REACTOME	R-HSA-428930
Thrombin signalling through proteinase activated receptors (PARs)	REACTOME	R-HSA-456926
Signal Transduction	REACTOME	R-HSA-162582
Signaling by GPCR	REACTOME	R-HSA-372790
GPCR downstream signaling	REACTOME	R-HSA-388396
G alpha (q) signalling events	REACTOME	R-HSA-416476
Gastrin-CREB signalling pathway via PKC and MAPK	REACTOME	R-HSA-881907
Metabolism	REACTOME	R-HSA-1430728
Integration of energy metabolism	REACTOME	R-HSA-163685
Regulation of insulin secretion	REACTOME	R-HSA-422356
Acetylcholine regulates insulin secretion	REACTOME	R-HSA-399997
Free fatty acids regulate insulin secretion	REACTOME	R-HSA-400451
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion	REACTOME	R-HSA-434316
Aldosterone synthesis and secretion	KEGG	hsa04925
Aldosterone synthesis and secretion	KEGG	ko04925

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PMIDs
PA27946	F2R	Gene	Pathway	associated	20938371
PA27949	F2RL3	Gene	Pathway	associated	20938371
PA32868	P2RY1	Gene	Pathway	associated	20938371
PA33384	PLCB1	Gene	Pathway	associated	20938371
PA33393	PLCG2	Gene	Pathway	associated	20938371
PA348	TBXA2R	Gene	Pathway	associated	20938371

References

Pubmed ID	Year	Title	Citations
37750536	2024	Papillary Hemangioma Harbors Somatic GNA11 and GNAQ Mutations.	1
37802294	2024	GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification.	2
38505749	2024	Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma.	0
37750536	2024	Papillary Hemangioma Harbors Somatic GNA11 and GNAQ Mutations.	1
37802294	2024	GNAQ/GNA11 Mosaicism Is Associated with Abnormal Serum Calcium Indices and Microvascular Neurocalcification.	2
38505749	2024	Double somatic mutations in CTNNB1 and GNA11 in an aldosterone-producing adenoma.	0
36970776	2023	GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.	2
36970776	2023	GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.	2
34260077	2022	Mixed vascular naevus syndrome: report of three children with somatic GNA11 mutation and new systemic associations.	1
35212356	2022	Genomic Profiling of Metastatic Uveal Melanoma Shows Frequent Coexisting BAP1 or SF3B1 and GNAQ/GNA11 Mutations and Correlation With Prognosis.	2
35580369	2022	In uveal melanoma Gα-protein GNA11 mutations convey a shorter disease-specific survival and are more strongly associated with loss of BAP1 and chromosomal alterations than Gα-protein GNAQ mutations.	12
35715928	2022	GNA11-mutated Sturge-Weber syndrome has distinct neurological and dermatological features.	4
36440997	2022	Early-onset hypertension associated with extensive cutaneous capillary malformations harboring postzygotic variants in GNAQ and GNA11.	1
34260077	2022	Mixed vascular naevus syndrome: report of three children with somatic GNA11 mutation and new systemic associations.	1
35212356	2022	Genomic Profiling of Metastatic Uveal Melanoma Shows Frequent Coexisting BAP1 or SF3B1 and GNAQ/GNA11 Mutations and Correlation With Prognosis.	2

Citation

Klaus G Griewank ; Swapna Vemula ; Boris C Bastian

GNA11 (guanine nucleotide binding protein (G protein), alpha 11 (Gq class))

Atlas Genet Cytogenet Oncol Haematol. 2011-03-01

Online version: http://atlasgeneticsoncology.org/gene/43272/css/gene-fusions/?id=43272