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NTSR1 (neurotensin receptor 1 (high affinity))

Written2014-10Sofiane 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)

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

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)NTR
HGNC (Hugo) NTSR1
HGNC Alias symbNTR
HGNC Previous nameneurotensin receptor 1 (high affinity)
LocusID (NCBI) 4923
Atlas_Id 44217
Location 20q13.33  [Link to chromosome band 20q13]
Location_base_pair Starts at 62708836 and ends at 62762771 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping NTSR1.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CCDC91 (12p11.22) / NTSR1 (20q13.33)RBFOX2 (22q12.3) / NTSR1 (20q13.33)
Note Neurotensin receptor 1 is the high affinity receptor for neurotensin, a 13 amino acid peptide with neurotransmitter and hormone functions.
Neurotensin binds 3 known receptors. Two of them belong to the superfamily of G-protein coupled receptors (GPCR): NTSR1 the high affinity receptor for neurotensin and NTSR2 its low affinity receptor, both belonging to GPCR class A (Mazella et al., 1996). The third receptor is NTR3 or sortilin, a member of VPS10 family (Petersen et al., 1997; Mazella et al., 1998).
NTSR1 through neurotensin binding is implicated in several functions, the modulation of dopaminergic systems, analgesia, and inhibition of food uptake, hypothermia, hypotension, intestinal motility and digestive secretions.

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.

Protein

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

Note
  
Entity 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 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 Malignant pleural mesothelioma
Note In malignant pleural mesothelioma, neurotensin and NTSR1 are significantly overexpressed in patients (Alifano et al., 2010a).
  
  
Entity 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 Prostatic cancer
Note NTSR1 is overexpressed in malignant prostatic tumors and malignant cell lines (Swift et al., 2010).
  
  
Entity 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 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 Glioblastoma
Note Neurotensin through NTSR1 activation is implicated in maintaining glioblastoma stem, depending on IL-8 and Stat3 pathways (Zhou et al., 2014).
  
  
Entity Melanoma
Note SR48692 through NTSR1 inhibition decreases melanoma cell proliferation and induces melanoma cell apoptosis (Zhang et al., 2014).
  
  
Entity Neurodegenerative and psychiatric diseases
Note Schizophrenia and Parkinson disease (Ferraro et al., 2014) and addiction (Ma et al., 2013).
  
  
Entity Inflammation
Note NTSR1 is overexpressed in colonic epithelial cells during inflammatory bowel diseases (Castagliuolo et al., 1999; Gui et al., 2013)
  

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Neurotensin (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, Wu Z, Dupouy S, Lupo AM, Mourra N, Takahashi T, Flejou JF, Tredaniel J, Regnard JF, Damotte D, Alifano M, Forgez P.
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PMID 25249545
 
Neurotensin receptor1 antagonist SR48692 reduces proliferation by inducing apoptosis and cell cycle arrest in melanoma cells.
Zhang Y, Zhu S, Yi L, Liu Y, Cui H.
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PMID 24357116
 
Neurotensin signaling regulates stem-like traits of glioblastoma stem cells through activation of IL-8/CXCR1/STAT3 pathway.
Zhou J, Yi L, Ouyang Q, Xu L, Cui H, Xu M.
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PMID 25200966
 

Citation

This paper should be referenced as such :
Sofiane Saada, Pierre Marget, Amazigh Abacci, Anne-Laure Fauchais, Marie-Odile Jauberteau
NTSR1 (neurotensin receptor 1 (high affinity))
Atlas Genet Cytogenet Oncol Haematol. 2015;19(10):617-620.
Free journal version : [ pdf ]   [ DOI ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  t(12;20)(p11;q13) CCDC91/NTSR1
t(20;22)(q13;q12) RBFOX2/NTSR1

External links

Nomenclature
HGNC (Hugo)NTSR1   8039
Cards
AtlasNTSR1ID44217ch20q13
Entrez_Gene (NCBI)NTSR1    neurotensin receptor 1
AliasesNTR
GeneCards (Weizmann)NTSR1
Ensembl hg19 (Hinxton)ENSG00000101188 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000101188 [Gene_View]  ENSG00000101188 [Sequence]  chr20:62708836-62762771 [Contig_View]  NTSR1 [Vega]
ICGC DataPortalENSG00000101188
TCGA cBioPortalNTSR1
AceView (NCBI)NTSR1
Genatlas (Paris)NTSR1
SOURCE (Princeton)NTSR1
Genetics Home Reference (NIH)NTSR1
Genomic and cartography
GoldenPath hg38 (UCSC)NTSR1  -     chr20:62708836-62762771 +  20q13.33   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)NTSR1  -     20q13.33   [Description]    (hg19-Feb_2009)
GoldenPathNTSR1 - 20q13.33 [CytoView hg19]  NTSR1 - 20q13.33 [CytoView hg38]
ImmunoBaseENSG00000101188
genome Data Viewer NCBINTSR1 [Mapview hg19]  
OMIM162651   
Gene and transcription
Genbank (Entrez)AY429106 BC040711 X70070
RefSeq transcript (Entrez)NM_002531
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)NTSR1
Alternative Splicing GalleryENSG00000101188
Gene ExpressionNTSR1 [ NCBI-GEO ]   NTSR1 [ EBI - ARRAY_EXPRESS ]   NTSR1 [ SEEK ]   NTSR1 [ MEM ]
Gene Expression Viewer (FireBrowse)NTSR1 [ Firebrowse - Broad ]
GenevisibleExpression of NTSR1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4923
GTEX Portal (Tissue expression)NTSR1
Human Protein AtlasENSG00000101188-NTSR1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP30989   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP30989  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP30989
Splice isoforms : SwissVarP30989
PhosPhoSitePlusP30989
Domaine pattern : Prosite (Expaxy)G_PROTEIN_RECEP_F1_1 (PS00237)    G_PROTEIN_RECEP_F1_2 (PS50262)   
Domains : Interpro (EBI)GPCR_Rhodpsn    GPCR_Rhodpsn_7TM    NT1_rcpt    NT_rcpt   
Domain families : Pfam (Sanger)7tm_1 (PF00001)   
Domain families : Pfam (NCBI)pfam00001   
Conserved Domain (NCBI)NTSR1
Blocks (Seattle)NTSR1
PDB (RSDB)2LYW    6OS9    6OSA    6PWC   
PDB Europe2LYW    6OS9    6OSA    6PWC   
PDB (PDBSum)2LYW    6OS9    6OSA    6PWC   
PDB (IMB)2LYW    6OS9    6OSA    6PWC   
Structural Biology KnowledgeBase2LYW    6OS9    6OSA    6PWC   
SCOP (Structural Classification of Proteins)2LYW    6OS9    6OSA    6PWC   
CATH (Classification of proteins structures)2LYW    6OS9    6OSA    6PWC   
SuperfamilyP30989
Human Protein Atlas [tissue]ENSG00000101188-NTSR1 [tissue]
Peptide AtlasP30989
HPRD01218
IPIIPI00028150   
Protein Interaction databases
DIP (DOE-UCLA)P30989
IntAct (EBI)P30989
BioGRIDNTSR1
STRING (EMBL)NTSR1
ZODIACNTSR1
Ontologies - Pathways
QuickGOP30989
Ontology : AmiGOtemperature homeostasis  negative regulation of systemic arterial blood pressure  regulation of membrane depolarization  G protein-coupled receptor activity  protein binding  mitochondrion  endoplasmic reticulum  Golgi apparatus  plasma membrane  integral component of plasma membrane  G protein-coupled receptor signaling pathway  neuropeptide signaling pathway  chemical synaptic transmission  learning  adult locomotory behavior  cytoplasmic side of plasma membrane  cell surface  positive regulation of glutamate secretion  positive regulation of gamma-aminobutyric acid secretion  G protein-coupled neurotensin receptor activity  G protein-coupled neurotensin receptor activity  symmetric synapse  response to lipid  identical protein binding  positive regulation of apoptotic process  negative regulation of apoptotic process  terminal bouton  dendritic spine  dendritic shaft  perikaryon  regulation of respiratory gaseous exchange  protein-containing complex binding  membrane raft  protein N-terminus binding  detection of temperature stimulus involved in sensory perception of pain  negative regulation of release of sequestered calcium ion into cytosol  positive regulation of release of sequestered calcium ion into cytosol  regulation of sensory perception of pain  positive regulation of inositol phosphate biosynthetic process  D-aspartate import across plasma membrane  inositol phosphate catabolic process  positive regulation of arachidonic acid secretion  positive regulation of inhibitory postsynaptic potential  L-glutamate import across plasma membrane  regulation of action potential  positive regulation of cation channel activity  
Ontology : EGO-EBItemperature homeostasis  negative regulation of systemic arterial blood pressure  regulation of membrane depolarization  G protein-coupled receptor activity  protein binding  mitochondrion  endoplasmic reticulum  Golgi apparatus  plasma membrane  integral component of plasma membrane  G protein-coupled receptor signaling pathway  neuropeptide signaling pathway  chemical synaptic transmission  learning  adult locomotory behavior  cytoplasmic side of plasma membrane  cell surface  positive regulation of glutamate secretion  positive regulation of gamma-aminobutyric acid secretion  G protein-coupled neurotensin receptor activity  G protein-coupled neurotensin receptor activity  symmetric synapse  response to lipid  identical protein binding  positive regulation of apoptotic process  negative regulation of apoptotic process  terminal bouton  dendritic spine  dendritic shaft  perikaryon  regulation of respiratory gaseous exchange  protein-containing complex binding  membrane raft  protein N-terminus binding  detection of temperature stimulus involved in sensory perception of pain  negative regulation of release of sequestered calcium ion into cytosol  positive regulation of release of sequestered calcium ion into cytosol  regulation of sensory perception of pain  positive regulation of inositol phosphate biosynthetic process  D-aspartate import across plasma membrane  inositol phosphate catabolic process  positive regulation of arachidonic acid secretion  positive regulation of inhibitory postsynaptic potential  L-glutamate import across plasma membrane  regulation of action potential  positive regulation of cation channel activity  
Pathways : KEGGCalcium signaling pathway    Neuroactive ligand-receptor interaction   
REACTOMEP30989 [protein]
REACTOME PathwaysR-HSA-416476 [pathway]   
NDEx NetworkNTSR1
Atlas of Cancer Signalling NetworkNTSR1
Wikipedia pathwaysNTSR1
Orthology - Evolution
OrthoDB4923
GeneTree (enSembl)ENSG00000101188
Phylogenetic Trees/Animal Genes : TreeFamNTSR1
HOGENOMP30989
Homologs : HomoloGeneNTSR1
Homology/Alignments : Family Browser (UCSC)NTSR1
Gene fusions - Rearrangements
Fusion : MitelmanCCDC91/NTSR1 [12p11.22/20q13.33]  
Fusion : MitelmanRBFOX2/NTSR1 [22q12.3/20q13.33]  
Fusion PortalCCDC91 12p11.22 NTSR1 20q13.33 LUAD
Fusion PortalRBFOX2 22q12.3 NTSR1 20q13.33 BRCA
Fusion : Fusion_HubCCDC91--NTSR1    IRF3--NTSR1    LAMA5--NTSR1    ODZ4--NTSR1    PGD--NTSR1    RBFOX2--NTSR1    TMEM189-UBE2V1--NTSR1   
Fusion : QuiverNTSR1
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNTSR1 [hg38]
dbVarNTSR1
ClinVarNTSR1
MonarchNTSR1
1000_GenomesNTSR1 
Exome Variant ServerNTSR1
GNOMAD BrowserENSG00000101188
Varsome BrowserNTSR1
Genomic Variants (DGV)NTSR1 [DGVbeta]
DECIPHERNTSR1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisNTSR1 
Mutations
ICGC Data PortalNTSR1 
TCGA Data PortalNTSR1 
Broad Tumor PortalNTSR1
OASIS PortalNTSR1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICNTSR1  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DNTSR1
Mutations and Diseases : HGMDNTSR1
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 NTSR1
DgiDB (Drug Gene Interaction Database)NTSR1
DoCM (Curated mutations)NTSR1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)NTSR1 (select a term)
intoGenNTSR1
NCG6 (London) select NTSR1
Cancer3DNTSR1(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM162651   
Orphanet
DisGeNETNTSR1
MedgenNTSR1
Genetic Testing Registry NTSR1
NextProtP30989 [Medical]
GENETestsNTSR1
Target ValidationNTSR1
Huge Navigator NTSR1 [HugePedia]
ClinGenNTSR1
Clinical trials, drugs, therapy
MyCancerGenomeNTSR1
Protein Interactions : CTD
Pharm GKB GenePA31821
PharosP30989
Clinical trialNTSR1
Miscellaneous
canSAR (ICR)NTSR1 (select the gene name)
HarmonizomeNTSR1
DataMed IndexNTSR1
Probes
Litterature
PubMed88 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXNTSR1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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