GRPR (Gastrin-Releasing Peptide Receptor)

2014-02-01   Terry W Moody 

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

Identity

HGNC
LOCATION
Xp22.2
LOCUSID
FUSION GENES

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.

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.

Proteins

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).
Atlas Image
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

Entity name
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 name
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 name
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 name
Colon cancer
Note
The GRPR regulates colon cancer cellular differentiation and impairs cellular metastasis (Carroll et al., 1999).
Entity name
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 name
Diabetes
Note
GRP-R knockout mice had impaired glucose tolerance due to a defect in insulin release (Persson et al., 2000).
Entity name
Satiety
Note
GRP-R blockade antagonizes feeding suppression by peripherally administered GRP (Ladenheim et al., 1996).
Entity name
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 name
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

Pubmed IDLast YearTitleAuthors
220804432011Bombesin antagonist-based radioligands for translational nuclear imaging of gastrin-releasing peptide receptor-positive tumors.Abiraj K et al
92118821997Identification of four amino acids in the gastrin-releasing peptide receptor that are required for high affinity agonist binding.Akeson M et al
55447311971Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes.Anastasi A et al
16711711991Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells.Battey JF et al
119607002002Contribution of gastrin-releasing peptide and its receptor to villus development in the murine and human gastrointestinal tract.Carroll RE et al
184831842008Human gastrin-releasing peptide receptor gene regulation requires transcription factor binding at two distinct CRE sites.Chinnappan D et al
163223382005Targeted cytotoxic bombesin analog AN-215 effectively inhibits experimental human breast cancers with a low induction of multi-drug resistance proteins.Engel JB et al
83836821993BRS-3: a novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells.Fathi Z et al
4923361979Bombesin suppresses feeding in rats.Gibbs J et al
194638752009Characterization of putative GRP- and NMB-receptor antagonist's interaction with human receptors.González N et al
92592691997Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene.Ishikawa-Brush Y et al
180555072008International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states.Jensen RT et al
2160151978Interaction of bombesin and litorin with specific membrane receptors on pancreatic acinar cells.Jensen RT et al
87602181996Hindbrain GRP receptor blockade antagonizes feeding suppression by peripherally administered GRP.Ladenheim EE et al
136798572003Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor.Lui VW et al
18484791991[Psi 13,14] bombesin analogues inhibit growth of small cell lung cancerin vitro and in vivo.Mahmoud S et al
235079302013Targeting GRPR in urological cancers--from basic research to clinical application.Mansi R et al
243778162014Gastrin-releasing peptide receptor expression in lung cancer.Mattei J et al
4969731979Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue.McDonald TJ et al
129091922003Nonpeptide gastrin releasing peptide receptor antagonists inhibit the proliferation of lung cancer cells.Moody TW et al
24431311987Bombesin-like peptides elevate cytosolic calcium in small cell lung cancer cells.Moody TW et al
2816861978Bomebesin: specific binding to rat brain membranes.Moody TW et al
110529492000Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice.Persson K et al
122390812002Islet function phenotype in gastrin-releasing peptide receptor gene-deficient mice.Persson K et al
119481252002Bombesin 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 et al
100922041998Signal transduction pathways in the mitogenic response to G protein-coupled neuropeptide receptor agonists.Rozengurt E et al
210344192011Bombesin receptor-mediated imaging and cytotoxicity: review and current status.Sancho V et al
183933812008Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders.Seidita G et al
17071291990Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor.Spindel ER et al
196613822009Cellular basis of itch sensation.Sun YG et al
114637902001Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor.Tokita K et al
18480801991cDNA cloning, characterization, and brain region-specific expression of a neuromedin-B-preferring bombesin receptor.Wada E et al
67992711982Bombesin stimulates prolactin and growth hormone release by pituitary cells in culture.Westendorf JM et al
63018511983Autoradiographic visualization of rat brain binding sites for bombesin-like peptides.Wolf SS et al
112459832001The human gastrin-releasing peptide receptor gene structure, its tissue expression and promoter.Xiao D et al
174311202007Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer.Zhang Q et al

Other Information

Locus ID:

NCBI: 2925
MIM: 305670
HGNC: 4609
Ensembl: ENSG00000126010

Variants:

dbSNP: 2925
ClinVar: 2925
TCGA: ENSG00000126010
COSMIC: GRPR

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000126010ENST00000380289P30550
ENSG00000126010ENST00000380289X5D7H2

Expression (GTEx)

0
1
2
3
4
5
6

Pathways

PathwaySourceExternal ID
Calcium signaling pathwayKEGGko04020
Neuroactive ligand-receptor interactionKEGGko04080
Calcium signaling pathwayKEGGhsa04020
Neuroactive ligand-receptor interactionKEGGhsa04080
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR ligand bindingREACTOMER-HSA-500792
Class A/1 (Rhodopsin-like receptors)REACTOMER-HSA-373076
Peptide ligand-binding receptorsREACTOMER-HSA-375276
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (q) signalling eventsREACTOMER-HSA-416476
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907

References

Pubmed IDYearTitleCitations
192047262009Transcriptomic and genetic studies identify IL-33 as a candidate gene for Alzheimer's disease.63
193437342009Expression of the gastrin-releasing peptide receptor, the prostate stem cell antigen and the prostate-specific membrane antigen in lymph node and bone metastases of prostate cancer.38
186766802008Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway.32
187536282008Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma.26
196921682010Genetic susceptibility to distinct bladder cancer subphenotypes.25
173496232007Gastrin-releasing peptide activates Akt through the epidermal growth factor receptor pathway and abrogates the effect of gefitinib.24
159671202005Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells.23
186633692010Panic disorder is associated with the serotonin transporter gene (SLC6A4) but not the promoter region (5-HTTLPR).23
282802212017Expression of Gastrin-Releasing Peptide Receptor in Breast Cancer and Its Association with Pathologic, Biologic, and Clinical Parameters: A Study of 1,432 Primary Tumors.15
124092262002GRP receptor-mediated immediate early gene expression and transcription factor Elk-1 activation in prostate cancer cells.14

Citation

Terry W Moody

GRPR (Gastrin-Releasing Peptide Receptor)

Atlas Genet Cytogenet Oncol Haematol. 2014-02-01

Online version: http://atlasgeneticsoncology.org/gene/40759/grpr