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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_namesneurotensin receptor 1 (high affinity)
Alias_symbol (synonym)NTR
Other alias
HGNC (Hugo) NTSR1
LocusID (NCBI) 4923
Atlas_Id 44217
Location 20q13.33  [Link to chromosome band 20q13]
Location_base_pair Starts at 61340189 and ends at 61394123 bp from pter ( according to hg19-Feb_2009)  [Mapping NTSR1.png]
Fusion genes
(updated 2016)
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)
  

Bibliography

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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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Neurotensin receptor1 antagonist SR48692 reduces proliferation by inducing apoptosis and cell cycle arrest in melanoma cells.
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Neurotensin signaling regulates stem-like traits of glioblastoma stem cells through activation of IL-8/CXCR1/STAT3 pathway.
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PMID 25200966
 

Citation

This paper should be referenced as such :
Saada S, Marget P, Abacci A, Fauchais AL, Jauberteau MO, Petit D, Lalloue F
NTSR1 (neurotensin receptor 1 (high affinity));
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/NTSR1ID44217ch20q13.html


External links

Nomenclature
HGNC (Hugo)NTSR1   8039
Cards
AtlasNTSR1ID44217ch20q13
Entrez_Gene (NCBI)NTSR1  4923  neurotensin receptor 1 (high affinity)
AliasesNTR
GeneCards (Weizmann)NTSR1
Ensembl hg19 (Hinxton)ENSG00000101188 [Gene_View]  chr20:61340189-61394123 [Contig_View]  NTSR1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000101188 [Gene_View]  chr20:61340189-61394123 [Contig_View]  NTSR1 [Vega]
ICGC DataPortalENSG00000101188
TCGA cBioPortalNTSR1
AceView (NCBI)NTSR1
Genatlas (Paris)NTSR1
WikiGenes4923
SOURCE (Princeton)NTSR1
Genetics Home Reference (NIH)NTSR1
Genomic and cartography
GoldenPath hg19 (UCSC)NTSR1  -     chr20:61340189-61394123 +  20q13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)NTSR1  -     20q13   [Description]    (hg38-Dec_2013)
EnsemblNTSR1 - 20q13 [CytoView hg19]  NTSR1 - 20q13 [CytoView hg38]
Mapping of homologs : NCBINTSR1 [Mapview hg19]  NTSR1 [Mapview hg38]
OMIM162651   
Gene and transcription
Genbank (Entrez)AY429106 BC040711 BC152809 X70070
RefSeq transcript (Entrez)NM_002531
RefSeq genomic (Entrez)NC_000020 NC_018931 NT_011362 NW_004929419
Consensus coding sequences : CCDS (NCBI)NTSR1
Cluster EST : UnigeneHs.590869 [ NCBI ]
CGAP (NCI)Hs.590869
Alternative Splicing GalleryENSG00000101188
Gene ExpressionNTSR1 [ NCBI-GEO ]   NTSR1 [ EBI - ARRAY_EXPRESS ]   NTSR1 [ SEEK ]   NTSR1 [ MEM ]
Gene Expression Viewer (FireBrowse)NTSR1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)4923
GTEX Portal (Tissue expression)NTSR1
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
DMDM Disease mutations4923
Blocks (Seattle)NTSR1
PDB (SRS)2LYW   
PDB (PDBSum)2LYW   
PDB (IMB)2LYW   
PDB (RSDB)2LYW   
Structural Biology KnowledgeBase2LYW   
SCOP (Structural Classification of Proteins)2LYW   
CATH (Classification of proteins structures)2LYW   
SuperfamilyP30989
Human Protein AtlasENSG00000101188
Peptide AtlasP30989
HPRD01218
IPIIPI00028150   
Protein Interaction databases
DIP (DOE-UCLA)P30989
IntAct (EBI)P30989
FunCoupENSG00000101188
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  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  protein homodimerization activity  positive regulation of apoptotic process  negative regulation of apoptotic process  terminal bouton  dendritic spine  dendritic shaft  perikaryon  regulation of respiratory gaseous exchange  membrane raft  protein heterodimerization activity  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  inositol phosphate catabolic process  positive regulation of arachidonic acid secretion  positive regulation of inhibitory postsynaptic potential  regulation of action potential  L-glutamate import into cell  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  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  protein homodimerization activity  positive regulation of apoptotic process  negative regulation of apoptotic process  terminal bouton  dendritic spine  dendritic shaft  perikaryon  regulation of respiratory gaseous exchange  membrane raft  protein heterodimerization activity  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  inositol phosphate catabolic process  positive regulation of arachidonic acid secretion  positive regulation of inhibitory postsynaptic potential  regulation of action potential  L-glutamate import into cell  positive regulation of cation channel activity  
Pathways : KEGGCalcium signaling pathway    Neuroactive ligand-receptor interaction   
REACTOMEP30989 [protein]
REACTOME Pathways375276 [pathway]   416476 [pathway]   
NDEx NetworkNTSR1
Atlas of Cancer Signalling NetworkNTSR1
Wikipedia pathwaysNTSR1
Orthology - Evolution
OrthoDB4923
GeneTree (enSembl)ENSG00000101188
Phylogenetic Trees/Animal Genes : TreeFamNTSR1
HOVERGENP30989
HOGENOMP30989
Homologs : HomoloGeneNTSR1
Homology/Alignments : Family Browser (UCSC)NTSR1
Gene fusions - Rearrangements
Fusion : MitelmanCCDC91/NTSR1 [12p11.22/20q13.33]  [t(12;20)(p11;q13)]  
Fusion : MitelmanRBFOX2/NTSR1 [22q12.3/20q13.33]  [t(20;22)(q13;q12)]  
Fusion: TCGACCDC91 12p11.22 NTSR1 20q13.33 LUAD
Fusion: TCGARBFOX2 22q12.3 NTSR1 20q13.33 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerNTSR1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)NTSR1
dbVarNTSR1
ClinVarNTSR1
1000_GenomesNTSR1 
Exome Variant ServerNTSR1
ExAC (Exome Aggregation Consortium)NTSR1 (select the gene name)
Genetic variants : HAPMAP4923
Genomic Variants (DGV)NTSR1 [DGVbeta]
DECIPHER (Syndromes)20:61340189-61394123  ENSG00000101188
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]  
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
NCG5 (London)NTSR1
Cancer3DNTSR1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM162651   
Orphanet
MedgenNTSR1
Genetic Testing Registry NTSR1
NextProtP30989 [Medical]
TSGene4923
GENETestsNTSR1
Huge Navigator NTSR1 [HugePedia]
snp3D : Map Gene to Disease4923
BioCentury BCIQNTSR1
ClinGenNTSR1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD4923
Chemical/Pharm GKB GenePA31821
Clinical trialNTSR1
Miscellaneous
canSAR (ICR)NTSR1 (select the gene name)
Probes
Litterature
PubMed67 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineNTSR1
EVEXNTSR1
GoPubMedNTSR1
iHOPNTSR1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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