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

Written2011-03Klaus G Griewank, Swapna Vemula, Boris C Bastian
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)

(Note : for Links provided by Atlas : click)

Identity

Alias_namesHHC2
hypocalciuric hypercalcemia 2
guanine nucleotide binding protein (G protein), alpha 11 (Gq class)
Alias_symbol (synonym)FBH
FBH2
FHH2
Other aliasGNA-11
GA11
HGNC (Hugo) GNA11
LocusID (NCBI) 2767
Atlas_Id 43272
Location 19p13.3  [Link to chromosome band 19p13]
Location_base_pair Starts at 3094410 and ends at 3124002 bp from pter ( according to hg19-Feb_2009)  [Mapping GNA11.png]
Local_order Between AES and AC0052641.
Fusion genes
(updated 2016)
GNA11 (19p13.3) / REG1A (2p12)NCLN (19p13.3) / GNA11 (19p13.3)REG1A (2p12) / GNA11 (19p13.3)

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.

Protein

 
  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
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

Note
  
Entity 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 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 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.
  

Bibliography

Reduced expression of GNA11 and silencing of MCT1 in human breast cancers.
Asada K, Miyamoto K, Fukutomi T, Tsuda H, Yagi Y, Wakazono K, Oishi S, Fukui H, Sugimura T, Ushijima T.
Oncology. 2003;64(4):380-8.
PMID 12759536
 
Functional importance of the amino terminus of Gq alpha.
Hepler JR, Biddlecome GH, Kleuss C, Camp LA, Hofmann SL, Ross EM, Gilman AG.
J Biol Chem. 1996 Jan 5;271(1):496-504.
PMID 8550609
 
Cell signalling diversity of the Gqalpha family of heterotrimeric G proteins.
Hubbard KB, Hepler JR.
Cell Signal. 2006 Feb;18(2):135-50. Epub 2005 Sep 22. (REVIEW)
PMID 16182515
 
Metastatic uveal melanoma.
Kivela T, Eskelin S, Kujala E.
Int Ophthalmol Clin. 2006 Winter;46(1):133-49. (REVIEW)
PMID 16365560
 
Activating mutations of the GNAQ gene: a frequent event in primary melanocytic neoplasms of the central nervous system.
Kusters-Vandevelde HV, Klaasen A, Kusters B, Groenen PJ, van Engen-van Grunsven IA, van Dijk MR, Reifenberger G, Wesseling P, Blokx WA.
Acta Neuropathol. 2009 Nov 22. [Epub ahead of print]
PMID 19936769
 
Mutational profile of GNAQQ209 in human tumors.
Lamba S, Felicioni L, Buttitta F, Bleeker FE, Malatesta S, Corbo V, Scarpa A, Rodolfo M, Knowles M, Frattini M, Marchetti A, Bardelli A.
PLoS One. 2009 Aug 31;4(8):e6833.
PMID 19718445
 
Structure of Galphaq-p63RhoGEF-RhoA complex reveals a pathway for the activation of RhoA by GPCRs.
Lutz S, Shankaranarayanan A, Coco C, Ridilla M, Nance MR, Vettel C, Baltus D, Evelyn CR, Neubig RR, Wieland T, Tesmer JJ.
Science. 2007 Dec 21;318(5858):1923-7.
PMID 18096806
 
Functions and regulatory mechanisms of Gq-signaling pathways.
Mizuno N, Itoh H.
Neurosignals. 2009;17(1):42-54. Epub 2009 Feb 12. (REVIEW)
PMID 19212139
 
Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.
Orth JH, Preuss I, Fester I, Schlosser A, Wilson BA, Aktories K.
Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7179-84. Epub 2009 Apr 15.
PMID 19369209
 
Prognostic implications of monosomy 3 in uveal melanoma.
Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R.
Lancet. 1996 May 4;347(9010):1222-5.
PMID 8622452
 
Uveal melanoma: epidemiologic aspects.
Singh AD, Bergman L, Seregard S.
Ophthalmol Clin North Am. 2005 Mar;18(1):75-84, viii. (REVIEW)
PMID 15763193
 
A novel Galphaq/11-selective inhibitor.
Takasaki J, Saito T, Taniguchi M, Kawasaki T, Moritani Y, Hayashi K, Kobori M.
J Biol Chem. 2004 Nov 12;279(46):47438-45. Epub 2004 Aug 31.
PMID 15339913
 
Mutations in GNA11 in uveal melanoma.
Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, Obenauf AC, Wackernagel W, Green G, Bouvier N, Sozen MM, Baimukanova G, Roy R, Heguy A, Dolgalev I, Khanin R, Busam K, Speicher MR, O'Brien J, Bastian BC.
N Engl J Med. 2010 Dec 2;363(23):2191-9. Epub 2010 Nov 17.
PMID 21083380
 
Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complex.
Waldo GL, Ricks TK, Hicks SN, Cheever ML, Kawano T, Tsuboi K, Wang X, Montell C, Kozasa T, Sondek J, Harden TK.
Science. 2010 Nov 12;330(6006):974-80. Epub 2010 Oct 21.
PMID 20966218
 
Characterization of G-protein alpha subunits in the Gq class: expression in murine tissues and in stromal and hematopoietic cell lines.
Wilkie TM, Scherle PA, Strathmann MP, Slepak VZ, Simon MI.
Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10049-53.
PMID 1946421
 

Citation

This paper should be referenced as such :
Griewank, KG ; Vemula, S ; Bastian, BC
GNA11 (guanine nucleotide binding protein (G protein), alpha 11 (Gq class))
Atlas Genet Cytogenet Oncol Haematol. 2011;15(10):828-830.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GNA11ID43272ch19p13.html


External links

Nomenclature
HGNC (Hugo)GNA11   4379
Cards
AtlasGNA11ID43272ch19p13
Entrez_Gene (NCBI)GNA11  2767  G protein subunit alpha 11
AliasesFBH; FBH2; FHH2; GNA-11; 
HHC2; HYPOC2
GeneCards (Weizmann)GNA11
Ensembl hg19 (Hinxton)ENSG00000088256 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000088256 [Gene_View]  chr19:3094410-3124002 [Contig_View]  GNA11 [Vega]
ICGC DataPortalENSG00000088256
TCGA cBioPortalGNA11
AceView (NCBI)GNA11
Genatlas (Paris)GNA11
WikiGenes2767
SOURCE (Princeton)GNA11
Genetics Home Reference (NIH)GNA11
Genomic and cartography
GoldenPath hg38 (UCSC)GNA11  -     chr19:3094410-3124002 +  19p13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GNA11  -     19p13.3   [Description]    (hg19-Feb_2009)
EnsemblGNA11 - 19p13.3 [CytoView hg19]  GNA11 - 19p13.3 [CytoView hg38]
Mapping of homologs : NCBIGNA11 [Mapview hg19]  GNA11 [Mapview hg38]
OMIM139313   
Gene and transcription
Genbank (Entrez)AB209435 AF011497 AF493900 AK091639 AL110227
RefSeq transcript (Entrez)NM_002067
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)GNA11
Cluster EST : UnigeneHs.654784 [ NCBI ]
CGAP (NCI)Hs.654784
Alternative Splicing GalleryENSG00000088256
Gene ExpressionGNA11 [ NCBI-GEO ]   GNA11 [ EBI - ARRAY_EXPRESS ]   GNA11 [ SEEK ]   GNA11 [ MEM ]
Gene Expression Viewer (FireBrowse)GNA11 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2767
GTEX Portal (Tissue expression)GNA11
Protein : pattern, domain, 3D structure
UniProt/SwissProtP29992   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP29992  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP29992
Splice isoforms : SwissVarP29992
PhosPhoSitePlusP29992
Domains : Interpro (EBI)Gprotein_alpha_Q    Gprotein_alpha_su    GproteinA_insert    P-loop_NTPase   
Domain families : Pfam (Sanger)G-alpha (PF00503)   
Domain families : Pfam (NCBI)pfam00503   
Domain families : Smart (EMBL)G_alpha (SM00275)  
Conserved Domain (NCBI)GNA11
DMDM Disease mutations2767
Blocks (Seattle)GNA11
SuperfamilyP29992
Human Protein AtlasENSG00000088256
Peptide AtlasP29992
HPRD00759
IPIIPI00305551   IPI00816520   IPI00470420   IPI00060933   
Protein Interaction databases
DIP (DOE-UCLA)P29992
IntAct (EBI)P29992
FunCoupENSG00000088256
BioGRIDGNA11
STRING (EMBL)GNA11
ZODIACGNA11
Ontologies - Pathways
QuickGOP29992
Ontology : AmiGOskeletal system development  action potential  photoreceptor outer segment  GTPase activity  GTPase activity  signal transducer activity  GTP binding  cytoplasm  lysosomal membrane  heterotrimeric G-protein complex  plasma membrane  signal transduction  adenylate cyclase-modulating G-protein coupled receptor signaling pathway  G-protein coupled acetylcholine receptor signaling pathway  heart development  phototransduction, visible light  entrainment of circadian clock  platelet activation  G-protein beta/gamma-subunit complex binding  type 2A serotonin receptor binding  regulation of melanocyte differentiation  metal ion binding  developmental pigmentation  phospholipase C-activating dopamine receptor signaling pathway  extracellular exosome  cellular response to pH  
Ontology : EGO-EBIskeletal system development  action potential  photoreceptor outer segment  GTPase activity  GTPase activity  signal transducer activity  GTP binding  cytoplasm  lysosomal membrane  heterotrimeric G-protein complex  plasma membrane  signal transduction  adenylate cyclase-modulating G-protein coupled receptor signaling pathway  G-protein coupled acetylcholine receptor signaling pathway  heart development  phototransduction, visible light  entrainment of circadian clock  platelet activation  G-protein beta/gamma-subunit complex binding  type 2A serotonin receptor binding  regulation of melanocyte differentiation  metal ion binding  developmental pigmentation  phospholipase C-activating dopamine receptor signaling pathway  extracellular exosome  cellular response to pH  
Pathways : BIOCARTABioactive Peptide Induced Signaling Pathway [Genes]   
Pathways : KEGG   
REACTOMEP29992 [protein]
REACTOME PathwaysR-HSA-456926 [pathway]   
NDEx NetworkGNA11
Atlas of Cancer Signalling NetworkGNA11
Wikipedia pathwaysGNA11
Orthology - Evolution
OrthoDB2767
GeneTree (enSembl)ENSG00000088256
Phylogenetic Trees/Animal Genes : TreeFamGNA11
HOVERGENP29992
HOGENOMP29992
Homologs : HomoloGeneGNA11
Homology/Alignments : Family Browser (UCSC)GNA11
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGNA11 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GNA11
dbVarGNA11
ClinVarGNA11
1000_GenomesGNA11 
Exome Variant ServerGNA11
ExAC (Exome Aggregation Consortium)GNA11 (select the gene name)
Genetic variants : HAPMAP2767
Genomic Variants (DGV)GNA11 [DGVbeta]
DECIPHERGNA11 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGNA11 
Mutations
ICGC Data PortalGNA11 
TCGA Data PortalGNA11 
Broad Tumor PortalGNA11
OASIS PortalGNA11 [ Somatic mutations - Copy number]
Cancer Gene: CensusGNA11 
Somatic Mutations in Cancer : COSMICGNA11  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGNA11
intOGen PortalGNA11
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GNA11
DgiDB (Drug Gene Interaction Database)GNA11
DoCM (Curated mutations)GNA11 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GNA11 (select a term)
intoGenGNA11
NCG5 (London)GNA11
Cancer3DGNA11(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM139313   
Orphanet5543    10453    11509    11510    14760   
MedgenGNA11
Genetic Testing Registry GNA11
NextProtP29992 [Medical]
TSGene2767
GENETestsGNA11
Target ValidationGNA11
Huge Navigator GNA11 [HugePedia]
snp3D : Map Gene to Disease2767
BioCentury BCIQGNA11
ClinGenGNA11
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2767
Chemical/Pharm GKB GenePA28764
Clinical trialGNA11
Miscellaneous
canSAR (ICR)GNA11 (select the gene name)
Probes
Litterature
PubMed103 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGNA11
EVEXGNA11
GoPubMedGNA11
iHOPGNA11
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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