NTSR1 (neurotensin receptor 1 (high affinity))

2014-10-01   Sofiane Saada , Pierre Marget , Amazigh Abacci , Anne-Laure Fauchais , Marie-Odile Jauberteau , Daniel Petit , Fabrice Lalloue 

Universite de Limoges, Equipe Accueil 3842 Homeostasie Cellulaire et Pathologies Limoges France (SS, PM, AA, ALF, MOJ, FL); Universite de Limoges, UMR INRA 1061 Unite de Genetique Moleculaire Animale , Limoges France (DP)

Identity

HGNC
LOCATION
20q13.33
LOCUSID
ALIAS
NTR
FUSION GENES

Abstract

Review on NTSR1, with data on DNA\/RNA, on the protein encoded and where the gene is implicated.

DNA/RNA

Description

The length of NTSR1 gene is 53.93 Kb, including 4 exons and 3 introns.

Transcription

Two transcripts are identified, a 4132 bp coding for a protein of 418 aa. The second contains 2950 bp but without yet identified coding protein.

Proteins

Description

NTSR1 (418 aa in human) belongs to the GPCR family containing 7 TM domains. Its structure contains 4 extracellular and intracellular loops, the N terminal amino acid extracellular part located in extra cellular region. Four glycosylation sites (extracellular) are reported as essential for the functions. The binding of neurotensin is depending on 6 aa of the 4th extracellular loop of the protein (Vincent et al., 1999).

Expression

In central nervous system, NTSR1 is expressed in substantia nigra, ventral tegmental area, amygdal nucleus, striatum and entorrhinal and prefrontal cortices (Kanba at al., 1986; Nicot et al., 1994).
In extra cerebral region, NTSR1 was detected in small intestine (Seybold et al., 1990; Mendez et al., 1997), fundus of stomach (Huidobro-Toro et al., 1985), pancreas (Wang et al., 2000), fetal liver (Ehrenfried et al., 1994), colon (Mendez et al., 1997) uterine tissue (Rodriguez et al., 2010) and prostate (Swift et al., 2010).
NTSR1 expression in human cells was reported in prostatic cells (Swift et al., 2010), colonic epithelial cells (Martin et al., 2002), lymphocytes (Evers et al., 1994) including T (Magazin et al., 2004) and B lymphocytes (Saada et al., 2012).

Localisation

In the cell membrane: Activation of NTSR1 through neurotensin binding needs some post translational events including glycosylation and palmitoylation to downstream heterotrimeric G protein subunits effectors. This lipidation allows its localization within cell membrane microdomains and enhances the interaction with Gαq /11 which mainly reside within structured microdomains. This NTSR-1-mediated MAPK signaling and cellular proliferation was demonstrated in breast cancer cells (Heakal et al., 2011).
Endocytosis: After activation by neurotensin, NTSR1 is desensitized through its internalization in endosomal vesicles in association with β-arrestin. This event requires phosphorylation depending on the C terminal region of NTSR1. Intracellular trafficking leads to NTSR1 degradation in lysosomes (Mazella and Vincent, 2006).

Function

NTSR1 is activated by neurotensin binding through autocrine or paracrine mechanism. Several signalizations were described depending on cell lines.
Indeed, neurotensin induces Erk phosphorylation colonic HT29 cells through PLC activation leading to Inositol phosphate formation (Massa et al., 2011).
The recruitment of G protein was described through NTSR1 activation in microdomains (Heakal et al., 2011).
In other cell types, cell proliferation, migration and invasion are depending on a transactivation of EGFR by NTSR1 (Amorino et al., 2007; Moody et al., 2014 ) or act through the increase of expression and activation of EGFR, HER2, HER3 (Younes et al., 2014; Dupouy et al., 2014).

Homology

The NTSR1 gene is conserved in Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog. 81 organisms have orthologs with human gene NTSR1.
Conservation during evolution:
NTSR1 gene is retrieved in jaw vertebrates (Gnathostomes) from the australian ghostshark, (Callorhinchus milii) to man, including most vertebrate groups (Teleosts, Coelacanth, the Amphibian Rana catesbeiana (Hwang et al., 2009), reptiles (python and lizard), birds and mammals. The duplication giving rise to NTSR1 and NTSR2 occurred probably in early vertebrates via the genome doubling (R2) events but details are unknown, as genes clearly encoding neurotensin receptors are doubtfully present in more basal vertebrates such as lampreys and hagfishes. Unlike its paralogue gene, NTSR1 was subject to positive selection in mammals, as numerous genes involved in chemosensory perception (Kosiol et al., 2008).

Implicated in

Entity name
Breast cancer
Note
NTSR1 is associated with the tumor grade and is a candidate risk factor involved in ductal breast cancer progression (Dupouy et al., 2009). Its functions in oncogenesis depend on EGFR, HER2 and HER3 expression in breast cancer cells (Dupouy et al., 2014).
Entity name
Lung cancer
Note
NTSR1 is overexpressed in lung cancer (Alifano et al., 2010b). Its activation enhances HER2, HER3 and EGFR expression in lung cancer (Younes et al., 2014). Pharmacological NTSR1 inhibitor (SR48692) inhibits EGFR activation (Moody et al., 2014).
Entity name
Malignant pleural mesothelioma
Note
In malignant pleural mesothelioma, neurotensin and NTSR1 are significantly overexpressed in patients (Alifano et al., 2010a).
Entity name
Head and neck squamous cell carcinomas
Note
NTSR1 contributed to cancer cell invasion and migration and is highly expressed in patients with metastasis (Shimizu et al., 2008).
Entity name
Prostatic cancer
Note
NTSR1 is overexpressed in malignant prostatic tumors and malignant cell lines (Swift et al., 2010).
Entity name
Pancreatic cancer
Note
An increase of NTSR1 expression is detected in human ductal pancreatic adenocarcinoma (Reubi et al., 1998; Wang et al., 2000) as well as in PANC-1 cell line (Wang et al., 2011).
Entity name
Colorectal cancer
Note
NTSR1 is associated with human cell proliferation (Massa et al., 2011), promotes tumor development in mouse colon cancer model (Bugni et al., 2012) and is overexpressed in colorectal cancer progression (Gui et al., 2008). NTSR1 activates miR-21 and miR-155, via Akt and NFkB, to down-regulate PTEN and SOCS1 and promote growth of tumors in mice. NTR1, miR-21, and miR-155 levels are increased in human colon tumor samples and correlate with tumor stage (Bakirtzi et al., 2011).
Entity name
Glioblastoma
Note
Neurotensin through NTSR1 activation is implicated in maintaining glioblastoma stem, depending on IL-8 and Stat3 pathways (Zhou et al., 2014).
Entity name
Melanoma
Note
SR48692 through NTSR1 inhibition decreases melanoma cell proliferation and induces melanoma cell apoptosis (Zhang et al., 2014).
Entity name
Neurodegenerative and psychiatric diseases
Note
Schizophrenia and Parkinson disease (Ferraro et al., 2014) and addiction (Ma et al., 2013).
Entity name
Inflammation
Note
NTSR1 is overexpressed in colonic epithelial cells during inflammatory bowel diseases (Castagliuolo et al., 1999; Gui et al., 2013)

Bibliography

Pubmed IDLast YearTitleAuthors
199321482010Neurotensin expression and outcome of malignant pleural mesothelioma.Alifano M et al
208103872010Neurotensin receptor 1 determines the outcome of non-small cell lung cancer.Alifano M et al
168621792007Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway.Amorino GP et al
218069462011Neurotensin signaling activates microRNAs-21 and -155 and Akt, promotes tumor growth in mice, and is increased in human colon tumors.Bakirtzi K et al
216302612012The neurotensin receptor-1 promotes tumor development in a sporadic but not an inflammation-associated mouse model of colon cancer.Bugni JM et al
100791051999Neurotensin is a proinflammatory neuropeptide in colonic inflammation.Castagliuolo I et al
191562132009The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression.Dupouy S et al
79446601994Expression of the neurotensin gene in fetal human liver and fibrolamellar carcinoma.Ehrenfried JA et al
80479781994Characterization of functional neurotensin receptors on human lymphocytes.Evers BM et al
251754572014Neurotensin NTS1-dopamine D2 receptor-receptor interactions in putative receptor heteromers: relevance for Parkinson's disease and schizophrenia.Ferraro L et al
213647412011Neurotensin receptor 1 is expressed in gastrointestinal stromal tumors but not in interstitial cells of Cajal.Gromova P et al
185413412008Increased neurotensin receptor-1 expression during progression of colonic adenocarcinoma.Gui X et al
154677632004Identification of 27 5' CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers.Hagihara A et al
217251972011Neurotensin receptor-1 inducible palmitoylation is required for efficient receptor-mediated mitogenic-signaling within structured membrane microdomains.Heakal Y et al
29886831985Excitatory neurotensin receptors on the smooth muscle of the rat fundus: possible implications in gastric motility.Huidobro-Toro JP et al
194563372009Phylogenetic history, pharmacological features, and signal transduction of neurotensin receptors in vertebrates.Hwang JI et al
39506141986Binding of [3H]neurotensin in human brain: properties and distribution.Kanba KS et al
186706502008Patterns of positive selection in six Mammalian genomes.Kosiol C et al
237437822013Association between neurotensin receptor 1 gene polymorphisms and alcohol dependence in a male Han Chinese population.Ma H et al
149620982004Sezary syndrome cells unlike normal circulating T lymphocytes fail to migrate following engagement of NT1 receptor.Magazin M et al
123604762002Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line.Martin S et al
219454422011Neurotensin-induced Erk1/2 phosphorylation and growth of human colonic cancer cells are independent from growth factors receptors activation.Massa F et al
87956171996Structure, functional expression, and cerebral localization of the levocabastine-sensitive neurotensin/neuromedin N receptor from mouse brain.Mazella J et al
169015852006Internalization and recycling properties of neurotensin receptors.Mazella J et al
97568511998The 100-kDa neurotensin receptor is gp95/sortilin, a non-G-protein-coupled receptor.Mazella J et al
94073901997High affinity neurotensin receptor mRNA distribution in rat brain and peripheral tissues. Analysis by quantitative RT-PCR.Méndez M et al
244960382014SR48692 inhibits non-small cell lung cancer proliferation in an EGF receptor-dependent manner.Moody TW et al
81954681994Neurotensin receptor expression in the rat forebrain and midbrain: a combined analysis by in situ hybridization and receptor autoradiography.Nicot A et al
90136111997Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography.Petersen CM et al
209598652011Genome-wide association of breast cancer: composite likelihood with imputed genotypes.Politopoulos I et al
115641782001Functional characterization of neurotensin receptors in human cutaneous T cell lymphoma malignant lymphocytes.Ramez M et al
96163181998Neurotensin receptors: a new marker for human ductal pancreatic adenocarcinoma.Reubi JC et al
205923072010Neurotensin and neurotensin receptor 1 expression in human myometrium and uterine leiomyomas.Rodríguez Y et al
231097252012Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in normal and malignant human B lymphocytes.Saada S et al
21690721990Neurotensin binding sites in porcine jejunum: biochemical characterization and intramural localization.Seybold VS et al
186615212008Identification of a novel therapeutic target for head and neck squamous cell carcinomas: a role for the neurotensin-neurotensin receptor 1 oncogenic signaling pathway.Shimizu S et al
200480802010Altered expression of neurotensin receptors is associated with the differentiation state of prostate cancer.Swift SL et al
103906491999Neurotensin and neurotensin receptors.Vincent JP et al
212729352011Pancreatic cancer bears overexpression of neurotensin and neurotensin receptor subtype-1 and SR 48692 counteracts neurotensin induced cell proliferation in human pancreatic ductal carcinoma cell line PANC-1.Wang JG et al
106905402000Neurotensin receptor-1 mRNA analysis in normal pancreas and pancreatic disease.Wang L et al
252495452014Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib.Younes M et al
243571162014Neurotensin receptor1 antagonist SR48692 reduces proliferation by inducing apoptosis and cell cycle arrest in melanoma cells.Zhang Y et al
252009662014Neurotensin signaling regulates stem-like traits of glioblastoma stem cells through activation of IL-8/CXCR1/STAT3 pathway.Zhou J et al

Other Information

Locus ID:

NCBI: 4923
MIM: 162651
HGNC: 8039
Ensembl: ENSG00000101188

Variants:

dbSNP: 4923
ClinVar: 4923
TCGA: ENSG00000101188
COSMIC: NTSR1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000101188ENST00000370501P30989

Expression (GTEx)

0
5
10
15
20
25
30
35
40

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
198745742009Genetical genomic determinants of alcohol consumption in rats and humans.93
123604762002Neurotensin receptor-1 and -3 complex modulates the cellular signaling of neurotensin in the HT29 cell line.34
157648102005Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation.34
190860532009Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.34
203989082010Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients.32
204680642010Association study of 182 candidate genes in anorexia nervosa.30
170185952006The neuromedin U-growth hormone secretagogue receptor 1b/neurotensin receptor 1 oncogenic signaling pathway as a therapeutic target for lung cancer.29
191562132009The neurotensin receptor-1 pathway contributes to human ductal breast cancer progression.28
208103872010Neurotensin receptor 1 determines the outcome of non-small cell lung cancer.26
262051052015Structural prerequisites for G-protein activation by the neurotensin receptor.25

Citation

Sofiane Saada ; Pierre Marget ; Amazigh Abacci ; Anne-Laure Fauchais ; Marie-Odile Jauberteau ; Daniel Petit ; Fabrice Lalloue

NTSR1 (neurotensin receptor 1 (high affinity))

Atlas Genet Cytogenet Oncol Haematol. 2014-10-01

Online version: http://atlasgeneticsoncology.org/gene/44217/ntsr1