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GRPR (Gastrin-Releasing Peptide Receptor)

Written2014-02Terry W Moody
National Cancer Institute, Center for Cancer Research, 9609 Medical Center Drive, Room 2W-130, Bethesda, MD 20892, USA

Abstract Bombesin (BB) and gastrin-releasing peptide (GRP) bind with high affinity to the GRP-receptor (GRP-R) which regulates release of gastrointestinal hormones, smooth muscle contraction and proliferation of epithelial as well as cancer cells. The GRP-R is a G-protein coupled receptor (GPCR) which activates phospholipase C signaling pathways. The GRP-R is expressed in numerous cancers including breast, colon, lung and prostate cancer.

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Identity

Alias_symbol (synonym)BB2
BB2R
Other alias
HGNC (Hugo) GRPR
LocusID (NCBI) 2925
Atlas_Id 40759
Location Xp22.2  [Link to chromosome band Xp22]
Location_base_pair Starts at 16141424 and ends at 16171641 bp from pter ( according to hg19-Feb_2009)  [Mapping GRPR.png]
Fusion genes
(updated 2016)
GRPR (Xp22.2) / SDC2 (8q22.1)SDC2 (8q22.1) / GRPR (Xp22.2)

DNA/RNA

Note The human GRP-R gene has 3 exons and is localized to chromosome Xp22.2.
Description The gene has 3 exons. The GRP-R gene spans 30218 bases.
Transcription The GRP-R gene has 9 and 3.1 kb transcripts in human stomach as well as NCI-H345 lung cancer cells, T47D breast cancer cells and HuTu 80 duodenal carcinoma cells. The pancreas has 9, 4.6, 3.1 and 2.1 kb transcripts. Polymorphisms are observed at 794 (G-A), 851 (C-T) and 1061 (C-T) but these do not alter the GRP-R sequence (Xiao et al., 2001). The GRP-R gene has 1155 bp.

Protein

Note Bombesin, a 14 amino acid peptide (Anastasi et al., 1974) and gastrin-releasing peptide (GRP), a 27 amino acid peptide (McDonald et al., 1979), bind with high affinity to receptors initially characterized in the rat brain (Moody et al., 1978) and guinea pig pancreatic acini (Jensen et al., 1978). The GRP-R was cloned (Battey et al., 1991; Spindel et al., 1990) and found to be a G-protein coupled receptor (GPCR) containing 384 amino acids. The human GRP-R gene is localized to the X chromosome and the GRP-R has 7 transmembrane (TM ) domains, an extracellular N-terminal and intracellular C-terminal. Exon 1 codes for TM 1, 2 and 3 domains with splice site in IC loop 2 (Asp137). Exon 2 codes for TM 4 and 5 with a Gln255 splice site. Exon 3 codes for TM 6-7 domains and the cytoplasmic C-terminal. Exon 1, 2 and 3 have 413 bp, 352 bp and 390 bp respectively whereas introns 1 and 2 are 23 kb and 1.6 kb respectively (Xiao et al., 2001).
The human GRP-R is glycosylated at Asn20, palmitoylated at Cys339 and has a disulfide between Cys113 and Cys196 (Jensen et al., 2008). For GRP-R agonist binding Gln120, Pro198, Arg287 and Ala307 are essential (Akeson et al., 1997). For GRP-R antagonist binding Thr296, Phe301 and Ser304 are essential (Tokita et al., 2001). GRP-R antagonists include (Psi13,14,Leu14)BB, (D-Phe6)BB6-13propylamide and PD176,252 (Gonzalez et al., 2009).
 
  Human GRP-R protein. The GRP-R, which is a glycoprotein embedded in the plasma membrane, contains 384 amino acids with 7 TM domains, an extracellular N-terminal and intracellular C-terminal. The amino acids at the N- and C-terminal are indicated. The amino acids before and after each of the 7 TM domains are indicated. Numerous amino acids in or near TM 2, 3, 4, 6 and 7 domains are essential for agonist binding, whereas amino acids in or near TM 6 and 7 domains are important for antagonist binding.
Description The GRP-R interacts with Gq causing phosphatidylinositol turnover (Rozengurt, 1998). As a result, BB addition to small cell lung cancer (SCLC) cells causes increased protein kinase C activity and elevation of cytosolic Ca2+ (Moody et al., 1987). Also, BB causes tyrosine phosphorylation of EGFR, ERK, FAK, paxillin, and Src leading to increased cellular proliferation (Jensen et al., 2008).
Expression The GRP-R is localized to the normal brain especially the periventricular nucleus (PVN) of the hypothalamus (Wolf et al., 1983) where activation by BB causes satiety (Gibbs et al., 1979). The GRP-R, which regulates insulin secretion, is present in the pancreatic islets (Persson et al., 2002). The GRP-R is present in colonic villi and may play a role in villi development (Carroll et al., 2002). The GRP-R is present on small cell lung cancer (SCLC) cells and BB stimulates whereas Psi13,14, Leu14)BB or PD176252 inhibits cellular proliferation (Mahmoud et al., 1991; Moody et al., 2003). The GRP-R is present on squamous cell carcinoma of the head and neck cancer cells and PD176252 inhibits the growth of these cells (Zhang et al., 2007). In colon cancer the transcription factor CREB is a regulator of GRP-R expression (Chinnappan et al., 2008).
Localisation The GRP-R is localized to the plasma membrane of normal and cancer cells.
Homology Other receptors of the BB family include neuromedin B (NMB) which contains 390 amino acids (Wada et al., 1991) and has 55% sequence homology with the GRP-R. An orphan receptor named BB receptor subtype 3 (BRS-3) was cloned which contains 399 amino acids and has 51% sequence homology with the GRP-R (Fathi et al., 1993). The GRP receptor binds BB and GRP with high affinity whereas the NMB receptor binds NMB with high affinity. BRS-3 does not bind BB, GRP or NMB with high affinity (Jensen et al., 2008).

Mutations

Note The GRP-R gene has 4 point mutations in biopsy specimens from patients with autism spectrum disorders, 2 of which result in amino acid changes (C6S and L181F). The mutated GRP-R had normal agonist binding and second messenger production (Seidita et al., 2008). Also an X-8 translocation occurs in intron 1 of the GRP-R gene in a patient with infantile autism (Ishikawa-Brush et al., 1997).

Implicated in

Note
  
Entity Lung cancer
Note High densities of GRP-R are present in SCLC and NSCLC biopsy specimens and cell lines (Mattei et al., 2014). BB stimulates whereas GRP-R antagonists such as PD176252 inhibit lung cancer cellular proliferation (Moody et al., 2003).
  
  
Entity Prostate cancer
Note Numerous radioligands have been developed to image the GRP-R in prostate cancer patients (Mansi et al., 2013; Sancho et al., 2011). GRP-R antagonists have been radiolabeled with (111)In, (99m)Tc, (68)Ga or (64)Cu (Abiraj et al., 2011). High tumor/background ratios were obtained as PET and SPECT images.
  
  
Entity Breast cancer
Note Cytotoxic BB conjugates of 2-pyrrolinodoxorubicin inhibit the growth of breast cancer xenografts in nude mice (Engel et al., 2005). The GRP-R was detected in 41/57 breast carcinoma biopsy specimens (Reubi et al., 2002).
  
  
Entity Colon cancer
Note The GRPR regulates colon cancer cellular differentiation and impairs cellular metastasis (Carroll et al., 1999).
  
  
Entity Head and neck cancer
Note The GRP-R regulates transactivation of the epidermal growth factor receptor in head and neck squamous cell carcinoma (Lui et al., 2003). The mitogenic effects of GRP require the activation of an EGFR-dependent MEK/ERK-dependent pathway.
  
  
Entity Diabetes
Note GRP-R knockout mice had impaired glucose tolerance due to a defect in insulin release (Persson et al., 2000).
  
  
Entity Satiety
Note GRP-R blockade antagonizes feeding suppression by peripherally administered GRP (Ladenheim et al., 1996).
  
  
Entity Hormone secretion
Note The GRP-R regulates the secretion of numerous hormones including gastrin, glucagon, insulin, pancreatic polypeptide, prolactin and somatostatin (Westendorf and Schonbrunn, 1982; Jensen et al., 2008).
  
  
Entity Pruritus
Note GRP-R containing spinal cord neurons, which are present in lamina I, mediate itch sensation (Sun et al., 2009). Addition of GRP-R antagonists inhibited scratching behavior in 3 mouse models of itching.
  

Bibliography

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PMID 492336
 
Characterization of putative GRP- and NMB-receptor antagonist's interaction with human receptors.
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PMID 19463875
 
Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene.
Ishikawa-Brush Y, Powell JF, Bolton P, Miller AP, Francis F, Willard HF, Lehrach H, Monaco AP.
Hum Mol Genet. 1997 Aug;6(8):1241-50.
PMID 9259269
 
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PMID 18055507
 
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Jensen RT, Moody T, Pert C, Rivier JE, Gardner JD.
Proc Natl Acad Sci U S A. 1978 Dec;75(12):6139-43.
PMID 216015
 
Hindbrain GRP receptor blockade antagonizes feeding suppression by peripherally administered GRP.
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PMID 8760218
 
Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor.
Lui VW, Thomas SM, Zhang Q, Wentzel AL, Siegfried JM, Li JY, Grandis JR.
Oncogene. 2003 Sep 18;22(40):6183-93.
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[Psi 13,14] bombesin analogues inhibit growth of small cell lung cancerin vitro and in vivo.
Mahmoud S, Staley J, Taylor J, Bogden A, Moreau JP, Coy D, Avis I, Cuttitta F, Mulshine JL, Moody TW.
Cancer Res. 1991 Apr 1;51(7):1798-802.
PMID 1848479
 
Targeting GRPR in urological cancers--from basic research to clinical application.
Mansi R, Fleischmann A, Macke HR, Reubi JC.
Nat Rev Urol. 2013 Apr;10(4):235-44. doi: 10.1038/nrurol.2013.42. Epub 2013 Mar 19. (REVIEW)
PMID 23507930
 
Gastrin-releasing peptide receptor expression in lung cancer.
Mattei J, Achcar RD, Cano CH, Macedo BR, Meurer L, Batlle BS, Groshong SD, Kulczynski JM, Roesler R, Dal Lago L, Brunetto AT, Schwartsmann G.
Arch Pathol Lab Med. 2014 Jan;138(1):98-104. doi: 10.5858/arpa.2012-0679-OA.
PMID 24377816
 
Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue.
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PMID 496973
 
Nonpeptide gastrin releasing peptide receptor antagonists inhibit the proliferation of lung cancer cells.
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PMID 12909192
 
Bombesin-like peptides elevate cytosolic calcium in small cell lung cancer cells.
Moody TW, Murphy A, Mahmoud S, Fiskum G.
Biochem Biophys Res Commun. 1987 Aug 31;147(1):189-95.
PMID 2443131
 
Bomebesin: specific binding to rat brain membranes.
Moody TW, Pert CB, Rivier J, Brown MR.
Proc Natl Acad Sci U S A. 1978 Nov;75(11):5372-6.
PMID 281686
 
Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice.
Persson K, Gingerich RL, Nayak S, Wada K, Wada E, Ahren B.
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PMID 11052949
 
Islet function phenotype in gastrin-releasing peptide receptor gene-deficient mice.
Persson K, Pacini G, Sundler F, Ahren B.
Endocrinology. 2002 Oct;143(10):3717-26.
PMID 12239081
 
Bombesin receptor subtypes in human cancers: detection with the universal radioligand (125)I-[D-TYR(6), beta-ALA(11), PHE(13), NLE(14)] bombesin(6-14).
Reubi JC, Wenger S, Schmuckli-Maurer J, Schaer JC, Gugger M.
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PMID 11948125
 
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Bombesin receptor-mediated imaging and cytotoxicity: review and current status.
Sancho V, Di Florio A, Moody TW, Jensen RT.
Curr Drug Deliv. 2011 Jan;8(1):79-134. (REVIEW)
PMID 21034419
 
Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders.
Seidita G, Mirisola M, D'Anna RP, Gallo A, Jensen RT, Mantey SA, Gonzalez N, Falco M, Zingale M, Elia M, Cucina L, Chiavetta V, Romano V, Cali F.
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Westendorf JM, Schonbrunn A.
Endocrinology. 1982 Feb;110(2):352-8.
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Citation

This paper should be referenced as such :
TW Moody
GRPR (Gastrin-Releasing Peptide Receptor)
Atlas Genet Cytogenet Oncol Haematol. 2014;18(10):711-714.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GRPRID40759chXp22.html


External links

Nomenclature
HGNC (Hugo)GRPR   4609
Cards
AtlasGRPRID40759chXp22
Entrez_Gene (NCBI)GRPR  2925  gastrin releasing peptide receptor
AliasesBB2
GeneCards (Weizmann)GRPR
Ensembl hg19 (Hinxton)ENSG00000126010 [Gene_View]  chrX:16141424-16171641 [Contig_View]  GRPR [Vega]
Ensembl hg38 (Hinxton)ENSG00000126010 [Gene_View]  chrX:16141424-16171641 [Contig_View]  GRPR [Vega]
ICGC DataPortalENSG00000126010
TCGA cBioPortalGRPR
AceView (NCBI)GRPR
Genatlas (Paris)GRPR
WikiGenes2925
SOURCE (Princeton)GRPR
Genetics Home Reference (NIH)GRPR
Genomic and cartography
GoldenPath hg19 (UCSC)GRPR  -     chrX:16141424-16171641 +  Xp22.2   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)GRPR  -     Xp22.2   [Description]    (hg38-Dec_2013)
EnsemblGRPR - Xp22.2 [CytoView hg19]  GRPR - Xp22.2 [CytoView hg38]
Mapping of homologs : NCBIGRPR [Mapview hg19]  GRPR [Mapview hg38]
OMIM305670   
Gene and transcription
Genbank (Entrez)AK313588 AU125660 BC074733 KJ534854 KJ534855
RefSeq transcript (Entrez)NM_005314
RefSeq genomic (Entrez)NC_000023 NC_018934 NG_012512 NT_167197 NW_004929438
Consensus coding sequences : CCDS (NCBI)GRPR
Cluster EST : UnigeneHs.567282 [ NCBI ]
CGAP (NCI)Hs.567282
Alternative Splicing GalleryENSG00000126010
Gene ExpressionGRPR [ NCBI-GEO ]   GRPR [ EBI - ARRAY_EXPRESS ]   GRPR [ SEEK ]   GRPR [ MEM ]
Gene Expression Viewer (FireBrowse)GRPR [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2925
GTEX Portal (Tissue expression)GRPR
Protein : pattern, domain, 3D structure
UniProt/SwissProtP30550   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP30550  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP30550
Splice isoforms : SwissVarP30550
PhosPhoSitePlusP30550
Domaine pattern : Prosite (Expaxy)G_PROTEIN_RECEP_F1_1 (PS00237)    G_PROTEIN_RECEP_F1_2 (PS50262)   
Domains : Interpro (EBI)Bombsn_rcpt-like    Gastrin_pep_rcpt    GPCR_Rhodpsn    GPCR_Rhodpsn_7TM   
Domain families : Pfam (Sanger)7tm_1 (PF00001)   
Domain families : Pfam (NCBI)pfam00001   
Conserved Domain (NCBI)GRPR
DMDM Disease mutations2925
Blocks (Seattle)GRPR
SuperfamilyP30550
Human Protein AtlasENSG00000126010
Peptide AtlasP30550
HPRD02376
IPIIPI00026881   IPI00815849   
Protein Interaction databases
DIP (DOE-UCLA)P30550
IntAct (EBI)P30550
FunCoupENSG00000126010
BioGRIDGRPR
STRING (EMBL)GRPR
ZODIACGRPR
Ontologies - Pathways
QuickGOP30550
Ontology : AmiGOplasma membrane  plasma membrane  integral component of plasma membrane  G-protein coupled receptor signaling pathway  cell proliferation  G-protein coupled peptide receptor activity  regulation of cell proliferation  
Ontology : EGO-EBIplasma membrane  plasma membrane  integral component of plasma membrane  G-protein coupled receptor signaling pathway  cell proliferation  G-protein coupled peptide receptor activity  regulation of cell proliferation  
Pathways : KEGGCalcium signaling pathway    Neuroactive ligand-receptor interaction   
REACTOMEP30550 [protein]
REACTOME Pathways375276 [pathway]   416476 [pathway]   
NDEx NetworkGRPR
Atlas of Cancer Signalling NetworkGRPR
Wikipedia pathwaysGRPR
Orthology - Evolution
OrthoDB2925
GeneTree (enSembl)ENSG00000126010
Phylogenetic Trees/Animal Genes : TreeFamGRPR
HOVERGENP30550
HOGENOMP30550
Homologs : HomoloGeneGRPR
Homology/Alignments : Family Browser (UCSC)GRPR
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGRPR [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GRPR
dbVarGRPR
ClinVarGRPR
1000_GenomesGRPR 
Exome Variant ServerGRPR
ExAC (Exome Aggregation Consortium)GRPR (select the gene name)
Genetic variants : HAPMAP2925
Genomic Variants (DGV)GRPR [DGVbeta]
DECIPHER (Syndromes)X:16141424-16171641  ENSG00000126010
CONAN: Copy Number AnalysisGRPR 
Mutations
ICGC Data PortalGRPR 
TCGA Data PortalGRPR 
Broad Tumor PortalGRPR
OASIS PortalGRPR [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGRPR  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGRPR
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
LOVD (Leiden Open Variation Database)X-chromosome gene database
BioMutasearch GRPR
DgiDB (Drug Gene Interaction Database)GRPR
DoCM (Curated mutations)GRPR (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GRPR (select a term)
intoGenGRPR
NCG5 (London)GRPR
Cancer3DGRPR(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM305670   
Orphanet
MedgenGRPR
Genetic Testing Registry GRPR
NextProtP30550 [Medical]
TSGene2925
GENETestsGRPR
Huge Navigator GRPR [HugePedia]
snp3D : Map Gene to Disease2925
BioCentury BCIQGRPR
ClinGenGRPR
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2925
Chemical/Pharm GKB GenePA29002
Clinical trialGRPR
Miscellaneous
canSAR (ICR)GRPR (select the gene name)
Probes
Litterature
PubMed59 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGRPR
EVEXGRPR
GoPubMedGRPR
iHOPGRPR
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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