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GPRC5A (G protein-coupled receptor, family C, group 5, member A)

Written2013-02Yuho Maki, Humam Kadara
Department of Thoracic/Head, Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesRAI3
retinoic acid induced 3
G protein-coupled receptor, class C, group 5, member A
Alias_symbol (synonym)RAIG1
TIG1
PEIG-1
HGNC (Hugo) GPRC5A
LocusID (NCBI) 9052
Atlas_Id 43793
Location 12p13.1  [Link to chromosome band 12p13]
Location_base_pair Starts at 13043956 and ends at 13066600 bp from pter ( according to hg19-Feb_2009)  [Mapping GPRC5A.png]
Local_order Between RPL13AP20 and GPRC5D genes.
Fusion genes
(updated 2016)
FAM234B (12p13.1) / GPRC5A (12p13.1)GPRC5A (12p13.1) / CSRNP3 (2q24.3)GPRC5A (12p13.1) / DSP (6p24.3)
GPRC5A (12p13.1) / XRN2 (20p11.23)RASSF7 (11p15.5) / GPRC5A (12p13.1)SRRM2 (16p13.3) / GPRC5A (12p13.1)
TG (8q24.22) / GPRC5A (12p13.1)

DNA/RNA

Note This gene encodes a member of the type 3 G protein-coupling receptor family, characterized by the signature 7-transmembrane domain motif. Through signaling with retinoic acid, it plays a critical role in development, cellular growth, and differentiation. The GPRC5A gene is not known at the present time to be amplified or lost in pathological disease including cancer. Mice with knockout of this gene were shown to develop spontaneous lung tumors.
Description The GPRC5A gene is composed of 12 exons spanning a region of 253002 bp.
Transcription There are several regulatory transcription factor binding sites in the GPRC5A promoter including p53, AP-1, c-Jun, STAT3, RAR, RXR, HFH-3 and LyF-1. For details see GeneCards.
Pseudogene There are no known pseudogenes.

Protein

Note This is a G-protein coupled receptor protein typified by its seven-pass transmembrane character. The GPRC5A transcript and protein are predominantly expressed in fetal and adult normal lung tissue as well as in kidney tissues suggesting a highly probably important role in the embryonic development and maturation of these organs. There are no major variants. Three variants have been described based on three single nucleotide polymorphisms. However, the functional consequence of these variants is currently unknown (see UniProt).
Description The GPRC5A protein is an orphan G-protein coupled receptor for which there is no known ligand yet. GPRC5A protein is composed of 357 amino acids. The GPRC5A protein is comprised of seven-transmembrane domains and regions as well as domains extracellular and four cytoplasmic domains. The protein is known to be glycosylated at residue 157. Moreover, studies have shown that this protein can be phosphorylated at Tyrosine residues 317, 320, 345, 347 and 350.
Expression The GPRC5A protein is expressed at high levels in fetal and adult normal lung tissue and expressed at low to moderate levels in various organ tissues including fetal kidney and adult placenta, kidney, prostate, testis, ovary, small intestine, colon, stomach, and spinal cord. It is not detectable in fetal heart, brain, and liver and adult heart, brain, liver, skeletal muscle, pancreas, spleen, thymus, and peripheral leukocytes. Analysis has shown that GPRC5A protein is low in murine and human lung tumors. GPRC5A protein is reduced in non-small cell lung cancers (NSCLCs) and in smoking-injured airway epithelium and in pathological lung conditions such as chronic obstructive pulmonary disease.
Localisation The GPRC5A protein was shown to be localized to the cell membrane, cytosol, golgi apparatus and endoplasmic reticulum.
Function GPRC5A was shown to be induced by retinoic acid treatment in head and neck and lung cancer cells. The function of GPRC5A is still poorly characterized. Limited studies from a few groups have demonstrated that this protein inhibits nuclear factor-kappa B signaling.
Homology Member of the G-protein coupled receptor 3 family and displays 67% homology with its murine counterpart.

Mutations

Note Mutations in this gene are poorly characterized. Non-somatic single nucleotide polymorphisms have been characterized however the functional consequence of these is unknown (see GeneCards).

Implicated in

Note
  
Entity Breast cancer
Note Limited studies have shown that human GPRC5A is elevated in human breast cancer specimens and promotes the growth of breast cancer cells.
  
  
Entity Lung cancer
Note GPRC5A is highly expressed in fetal and adult normal lung tissue suggesting that it plays important roles in the embryonic development, maturation and differentiation of these epithelial organs. A study has shown that mice with knockout of both alleles of this gene developed lung adenomas and adenocarcinomas at 12 months onwards at a much higher rate compared to their wild type littermates. The incidence and size of lung tumors was substantially and significantly increased following exposure of Gprc5a knockout mice to the tobacco-specific carcinogen NNK. Moreover, another study derived a gene expression signature from non-malignant lung epithelial Gprc5a knockout and wild type cells and showed that this signature, indicating GPRC5A loss, was associated with poor survival and prognosis in human lung cancer following cross-comparative analysis of human lung cancer microarray datasets. Mechanistically, loss of Gprc5a was shown to induce constitutive activation of the Nf-kB transcriptional factor leading to observed acidic macrophage pneumonia and inflammation in the lung and subsequent increased cellular migration, invasion and oncogenesis. Moreover, loss of Gprc5a was shown to increase JAK/STAT signaling in turn causing elevated cell growth, proliferation and survival. Further, and in accordance with the previous findings of GPRC5A-mediated inhibition of NF-kB, treatment of Gprc5a knockout mice with NTHI increased the severity of observed adenomas implicating inflammation in the course of carcinogenesis downstream of Gprc5a loss.
Disease Non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, adenomas.
Prognosis A gene-expression signature indicating loss of Gprc5A was derived by comparing transcriptome of non-malignant Gprc5a knockout cells compared to wild type cells. This expression signature was found to be highly predictive of poor survival and prognosis in human lung cancer and in particular in human lung adenocarcinomas.
  
  
Entity Chronic obstructive pulmonary disease (COPD)
Note GPRC5A protein, analyzed by immunohistochemical analysis, was shown to be decreased in histologically normal bronchial airway epithelia in COPD patients compared to normal airways from phenotypically normal non-smokers and smokers. Moreover, GPRC5A immunohistochemical protein expression was further decreased in normal bronchial epithelia of patients with both COPD and NSCLC. Given the field cancerization principle and the predisposition of COPD patients to lung cancer, these findings suggest that the GPRC5A protein may be implicated in COPD-associated lung cancer development.
Disease Lung cancer.
  

Bibliography

GPRC5A: A potential tumor suppressor and oncogene.
Acquafreda T, Soprano KJ, Soprano DR.
Cancer Biol Ther. 2009 May;8(10):963-5.
PMID 19593893
 
Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation.
Barta P, Van Pelt C, Men T, Dickey BF, Lotan R, Moghaddam SJ.
Mol Cancer. 2012 Jan 12;11:4. doi: 10.1186/1476-4598-11-4.
PMID 22239913
 
Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor.
Chen Y, Deng J, Fujimoto J, Kadara H, Men T, Lotan D, Lotan R.
Cancer Res. 2010 Nov 1;70(21):8917-26. doi: 10.1158/0008-5472.CAN-10-0518. Epub 2010 Oct 19.
PMID 20959490
 
Molecular cloning and characterization of a novel retinoic acid-inducible gene that encodes a putative G protein-coupled receptor.
Cheng Y, Lotan R.
J Biol Chem. 1998 Dec 25;273(52):35008-15.
PMID 9857033
 
Knockout of the tumor suppressor gene Gprc5a in mice leads to NF-kappaB activation in airway epithelium and promotes lung inflammation and tumorigenesis.
Deng J, Fujimoto J, Ye XF, Men TY, Van Pelt CS, Chen YL, Lin XF, Kadara H, Tao Q, Lotan D, Lotan R.
Cancer Prev Res (Phila). 2010 Apr;3(4):424-37. doi: 10.1158/1940-6207.CAPR-10-0032. Epub 2010 Mar 30.
PMID 20354164
 
G-protein coupled receptor family C, group 5, member A (GPRC5A) expression is decreased in the adjacent field and normal bronchial epithelia of patients with chronic obstructive pulmonary disease and non-small-cell lung cancer.
Fujimoto J, Kadara H, Garcia MM, Kabbout M, Behrens C, Liu DD, Lee JJ, Solis LM, Kim ES, Kalhor N, Moran C, Sharafkhaneh A, Lotan R, Wistuba II.
J Thorac Oncol. 2012 Dec;7(12):1747-54. doi: 10.1097/JTO.0b013e31826bb1ff.
PMID 23154545
 
Novel reciprocal regulation of cAMP signaling and apoptosis by orphan G-protein-coupled receptor GPRC5A gene expression.
Hirano M, Zang L, Oka T, Ito Y, Shimada Y, Nishimura Y, Tanaka T.
Biochem Biophys Res Commun. 2006 Dec 8;351(1):185-91. Epub 2006 Oct 11.
PMID 17055459
 
Production and characterisation of monoclonal antibodies against RAI3 and its expression in human breast cancer.
Jorissen H, Bektas N, Dahl E, Hartmann A, ten Haaf A, Di Fiore S, Kiefer H, Thess A, Barth S, Klockenbring T.
BMC Cancer. 2009 Jun 24;9:200. doi: 10.1186/1471-2407-9-200.
PMID 19552806
 
A Gprc5a tumor suppressor loss of expression signature is conserved, prevalent, and associated with survival in human lung adenocarcinomas.
Kadara H, Fujimoto J, Men T, Ye X, Lotan D, Lee JS, Lotan R.
Neoplasia. 2010 Jun;12(6):499-505.
PMID 20563252
 
Identification of RAI3 as a therapeutic target for breast cancer.
Nagahata T, Sato T, Tomura A, Onda M, Nishikawa K, Emi M.
Endocr Relat Cancer. 2005 Mar;12(1):65-73.
PMID 15788639
 
A new tumor suppressor gene, selective for lung cancer.
Sporn MB.
J Natl Cancer Inst. 2007 Nov 21;99(22):1654-5. Epub 2007 Nov 13.
PMID 18000215
 
Identification of the retinoic acid-inducible Gprc5a as a new lung tumor suppressor gene.
Tao Q, Fujimoto J, Men T, Ye X, Deng J, Lacroix L, Clifford JL, Mao L, Van Pelt CS, Lee JJ, Lotan D, Lotan R.
J Natl Cancer Inst. 2007 Nov 21;99(22):1668-82. Epub 2007 Nov 13.
PMID 18000218
 
Integrative genomics revealed RAI3 is a cell growth-promoting gene and a novel P53 transcriptional target.
Wu Q, Ding W, Mirza A, Van Arsdale T, Wei I, Bishop WR, Basso A, McClanahan T, Luo L, Kirschmeier P, Gustafson E, Hernandez M, Liu S.
J Biol Chem. 2005 Apr 1;280(13):12935-43. Epub 2005 Jan 18.
PMID 15659406
 
Mechanisms underlying the induction of the putative human tumor suppressor GPRC5A by retinoic acid.
Ye X, Tao Q, Wang Y, Cheng Y, Lotan R.
Cancer Biol Ther. 2009 May;8(10):951-62. Epub 2009 May 20.
PMID 19279407
 

Citation

This paper should be referenced as such :
Maki, Y ; Kadara, H
GPRC5A (G protein-coupled receptor, family C, group 5, member A)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(8):523-525.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GPRC5AID43793ch12p13.html


External links

Nomenclature
HGNC (Hugo)GPRC5A   9836
Cards
AtlasGPRC5AID43793ch12p13
Entrez_Gene (NCBI)GPRC5A  9052  G protein-coupled receptor class C group 5 member A
AliasesGPCR5A; PEIG-1; RAI3; RAIG1; 
TIG1
GeneCards (Weizmann)GPRC5A
Ensembl hg19 (Hinxton)ENSG00000013588 [Gene_View]  chr12:13043956-13066600 [Contig_View]  GPRC5A [Vega]
Ensembl hg38 (Hinxton)ENSG00000013588 [Gene_View]  chr12:13043956-13066600 [Contig_View]  GPRC5A [Vega]
ICGC DataPortalENSG00000013588
TCGA cBioPortalGPRC5A
AceView (NCBI)GPRC5A
Genatlas (Paris)GPRC5A
WikiGenes9052
SOURCE (Princeton)GPRC5A
Genetics Home Reference (NIH)GPRC5A
Genomic and cartography
GoldenPath hg19 (UCSC)GPRC5A  -     chr12:13043956-13066600 +  12p13.1   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)GPRC5A  -     12p13.1   [Description]    (hg38-Dec_2013)
EnsemblGPRC5A - 12p13.1 [CytoView hg19]  GPRC5A - 12p13.1 [CytoView hg38]
Mapping of homologs : NCBIGPRC5A [Mapview hg19]  GPRC5A [Mapview hg38]
OMIM604138   
Gene and transcription
Genbank (Entrez)AF095448 AF506289 AI587426 AK001761 AK122672
RefSeq transcript (Entrez)NM_003979
RefSeq genomic (Entrez)NC_000012 NC_018923 NT_009714 NW_004929383
Consensus coding sequences : CCDS (NCBI)GPRC5A
Cluster EST : UnigeneHs.631733 [ NCBI ]
CGAP (NCI)Hs.631733
Alternative Splicing GalleryENSG00000013588
Gene ExpressionGPRC5A [ NCBI-GEO ]   GPRC5A [ EBI - ARRAY_EXPRESS ]   GPRC5A [ SEEK ]   GPRC5A [ MEM ]
Gene Expression Viewer (FireBrowse)GPRC5A [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9052
GTEX Portal (Tissue expression)GPRC5A
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8NFJ5   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8NFJ5  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8NFJ5
Splice isoforms : SwissVarQ8NFJ5
PhosPhoSitePlusQ8NFJ5
Domains : Interpro (EBI)GPCR_3_C   
Domain families : Pfam (Sanger)7tm_3 (PF00003)   
Domain families : Pfam (NCBI)pfam00003   
Conserved Domain (NCBI)GPRC5A
DMDM Disease mutations9052
Blocks (Seattle)GPRC5A
SuperfamilyQ8NFJ5
Human Protein AtlasENSG00000013588
Peptide AtlasQ8NFJ5
HPRD16037
IPIIPI00022624   IPI01011397   IPI01010964   
Protein Interaction databases
DIP (DOE-UCLA)Q8NFJ5
IntAct (EBI)Q8NFJ5
FunCoupENSG00000013588
BioGRIDGPRC5A
STRING (EMBL)GPRC5A
ZODIACGPRC5A
Ontologies - Pathways
QuickGOQ8NFJ5
Ontology : AmiGOG-protein coupled receptor activity  protein binding  plasma membrane  integral component of plasma membrane  signal transduction  negative regulation of epidermal growth factor-activated receptor activity  G-protein coupled receptor signaling pathway  cytoplasmic vesicle membrane  intracellular membrane-bounded organelle  extracellular exosome  
Ontology : EGO-EBIG-protein coupled receptor activity  protein binding  plasma membrane  integral component of plasma membrane  signal transduction  negative regulation of epidermal growth factor-activated receptor activity  G-protein coupled receptor signaling pathway  cytoplasmic vesicle membrane  intracellular membrane-bounded organelle  extracellular exosome  
NDEx NetworkGPRC5A
Atlas of Cancer Signalling NetworkGPRC5A
Wikipedia pathwaysGPRC5A
Orthology - Evolution
OrthoDB9052
GeneTree (enSembl)ENSG00000013588
Phylogenetic Trees/Animal Genes : TreeFamGPRC5A
HOVERGENQ8NFJ5
HOGENOMQ8NFJ5
Homologs : HomoloGeneGPRC5A
Homology/Alignments : Family Browser (UCSC)GPRC5A
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGPRC5A [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GPRC5A
dbVarGPRC5A
ClinVarGPRC5A
1000_GenomesGPRC5A 
Exome Variant ServerGPRC5A
ExAC (Exome Aggregation Consortium)GPRC5A (select the gene name)
Genetic variants : HAPMAP9052
Genomic Variants (DGV)GPRC5A [DGVbeta]
DECIPHER (Syndromes)12:13043956-13066600  ENSG00000013588
CONAN: Copy Number AnalysisGPRC5A 
Mutations
ICGC Data PortalGPRC5A 
TCGA Data PortalGPRC5A 
Broad Tumor PortalGPRC5A
OASIS PortalGPRC5A [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGPRC5A  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGPRC5A
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 GPRC5A
DgiDB (Drug Gene Interaction Database)GPRC5A
DoCM (Curated mutations)GPRC5A (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GPRC5A (select a term)
intoGenGPRC5A
NCG5 (London)GPRC5A
Cancer3DGPRC5A(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM604138   
Orphanet
MedgenGPRC5A
Genetic Testing Registry GPRC5A
NextProtQ8NFJ5 [Medical]
TSGene9052
GENETestsGPRC5A
Huge Navigator GPRC5A [HugePedia]
snp3D : Map Gene to Disease9052
BioCentury BCIQGPRC5A
ClinGenGPRC5A
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9052
Chemical/Pharm GKB GenePA34194
Clinical trialGPRC5A
Miscellaneous
canSAR (ICR)GPRC5A (select the gene name)
Probes
Litterature
PubMed31 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGPRC5A
EVEXGPRC5A
GoPubMedGPRC5A
iHOPGPRC5A
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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