Human Gene NOTCH2 (ENST00000256646.7)
  Description: Homo sapiens notch receptor 2 (NOTCH2), transcript variant 1, mRNA. (from RefSeq NM_024408)
RefSeq Summary (NM_024408): This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011].
Gencode Transcript: ENST00000256646.7
Gencode Gene: ENSG00000134250.20
Transcript (Including UTRs)
   Position: hg38 chr1:119,911,553-120,069,662 Size: 158,110 Total Exon Count: 34 Strand: -
Coding Region
   Position: hg38 chr1:119,915,306-120,069,406 Size: 154,101 Coding Exon Count: 34 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesGeneReviewsMethods
Data last updated at UCSC: 2021-01-14 15:32:12

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr1:119,911,553-120,069,662)mRNA (may differ from genome)Protein (2471 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaBioGPS
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PubMedReactomeUniProtKBWikipedia

-  Comments and Description Text from UniProtKB
  ID: NOTC2_HUMAN
DESCRIPTION: RecName: Full=Neurogenic locus notch homolog protein 2; Short=Notch 2; Short=hN2; Contains: RecName: Full=Notch 2 extracellular truncation; Contains: RecName: Full=Notch 2 intracellular domain; Flags: Precursor;
FUNCTION: Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation.
SUBUNIT: Heterodimer of a C-terminal fragment N(TM) and an N- terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2. Interacts with RELA/p65 (By similarity). Interacts with HIF1AN.
SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein.
SUBCELLULAR LOCATION: Notch 2 intracellular domain: Nucleus. Note=Following proteolytical processing NICD is translocated to the nucleus.
TISSUE SPECIFICITY: Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.
PTM: Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form. Cleavage results in a C- terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).
PTM: Hydroxylated by HIF1AN.
DISEASE: Defects in NOTCH2 are the cause of Alagille syndrome type 2 (ALGS2) [MIM:610205]. Alagille syndrome is an autosomal dominant multisystem disorder defined clinically by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems.
DISEASE: Defects in NOTCH2 are the cause of Hajdu-Cheney syndrome (HJCYS) [MIM:102500]. A rare skeletal disorder characterized by the association of facial anomalies, acro-osteolysis, general osteoporosis, insufficient ossification of the skull, and periodontal disease (premature loss of permanent teeth). Other features include cleft palate, congenital heart defects, polycystic kidneys, orthopedic problems and anomalies of the genitalia, intestines and eyes. Note=NOTCH2 mutations associated with Hajdu-Cheney syndrome cluster to the last coding exon of the gene. This suggests that the mutant mRNA products may escape nonsense-mediated decay and the resulting truncated NOTCH2 proteins act in a gain-of-function manner.
SIMILARITY: Belongs to the NOTCH family.
SIMILARITY: Contains 6 ANK repeats.
SIMILARITY: Contains 35 EGF-like domains.
SIMILARITY: Contains 3 LNR (Lin/Notch) repeats.
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/NOTCH2ID41556ch1p12.html";
WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/NOTCH2";

-  MalaCards Disease Associations
  MalaCards Gene Search: NOTCH2
Diseases sorted by gene-association score: alagille syndrome 2* (1579), hajdu-cheney syndrome* (1039), notch2-related alagille syndrome* (500), acroosteolysis dominant type* (400), alagille syndrome 1* (90), lacrimal gland adenoid cystic carcinoma (23), splenic marginal zone lymphoma (18), nodular regenerative hyperplasia (7), lacrimal gland adenocarcinoma (6), chromosome 10q26 deletion syndrome (6), spondylocostal dysostosis 3, autosomal recessive (5), renal-hepatic-pancreatic dysplasia (5), persistent mullerian duct syndrome (4), dowling-degos disease (4), osteoporosis (3), chronic lymphocytic leukemia (2)
* = Manually curated disease association

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 25.20 RPKM in Cells - Cultured fibroblasts
Total median expression: 470.46 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -118.60256-0.463 Picture PostScript Text
3' UTR -1015.003753-0.270 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR002110 - Ankyrin_rpt
IPR020683 - Ankyrin_rpt-contain_dom
IPR024600 - DUF3454_notch
IPR000742 - EG-like_dom
IPR001881 - EGF-like_Ca-bd
IPR013032 - EGF-like_CS
IPR000152 - EGF-type_Asp/Asn_hydroxyl_site
IPR018097 - EGF_Ca-bd_CS
IPR008297 - Notch
IPR022336 - Notch_2
IPR000800 - Notch_dom
IPR010660 - Notch_NOD_dom
IPR011656 - Notch_NODP_dom

Pfam Domains:
PF00023 - Ankyrin repeat
PF12796 - Ankyrin repeats (3 copies)
PF11936 - Domain of unknown function (DUF3454)
PF00008 - EGF-like domain
PF07645 - Calcium-binding EGF domain
PF06816 - NOTCH protein
PF07684 - NOTCH protein
PF00066 - LNR domain

Protein Data Bank (PDB) 3-D Structure
MuPIT help

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- X-ray MuPIT


ModBase Predicted Comparative 3D Structure on Q04721
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-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologGenome BrowserGenome BrowserNo ortholog
Gene Details     
Gene Sorter     
MGI EnsemblEnsemblWormBase 
Protein SequenceProtein Sequence Protein SequenceProtein Sequence 
AlignmentAlignment AlignmentAlignment 

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0005509 calcium ion binding
GO:0005515 protein binding
GO:0038023 signaling receptor activity
GO:0038049 transcription factor activity, ligand-activated RNA polymerase II transcription factor binding

Biological Process:
GO:0001709 cell fate determination
GO:0002315 marginal zone B cell differentiation
GO:0003184 pulmonary valve morphogenesis
GO:0006351 transcription, DNA-templated
GO:0006355 regulation of transcription, DNA-templated
GO:0006367 transcription initiation from RNA polymerase II promoter
GO:0006915 apoptotic process
GO:0007050 cell cycle arrest
GO:0007219 Notch signaling pathway
GO:0007275 multicellular organism development
GO:0007399 nervous system development
GO:0009887 animal organ morphogenesis
GO:0010629 negative regulation of gene expression
GO:0019827 stem cell population maintenance
GO:0030097 hemopoiesis
GO:0030154 cell differentiation
GO:0030522 intracellular receptor signaling pathway
GO:0043066 negative regulation of apoptotic process
GO:0045967 negative regulation of growth rate
GO:0046579 positive regulation of Ras protein signal transduction
GO:0046849 bone remodeling
GO:0050793 regulation of developmental process
GO:0060413 atrial septum morphogenesis
GO:0061314 Notch signaling involved in heart development
GO:0070374 positive regulation of ERK1 and ERK2 cascade
GO:2001204 regulation of osteoclast development

Cellular Component:
GO:0000139 Golgi membrane
GO:0005576 extracellular region
GO:0005634 nucleus
GO:0005654 nucleoplasm
GO:0005737 cytoplasm
GO:0005789 endoplasmic reticulum membrane
GO:0005886 plasma membrane
GO:0005887 integral component of plasma membrane
GO:0009986 cell surface
GO:0016020 membrane
GO:0016021 integral component of membrane
GO:0043235 receptor complex


-  Descriptions from all associated GenBank mRNAs
  AF315356 - Homo sapiens NOTCH2 protein (NOTCH2) mRNA, complete cds.
AF308601 - Homo sapiens NOTCH 2 (N2) mRNA, complete cds.
U77493 - Human Notch2 mRNA, partial cds.
BC071562 - Homo sapiens Notch homolog 2 (Drosophila), mRNA (cDNA clone MGC:87008 IMAGE:4822955), complete cds.
KJ901607 - Synthetic construct Homo sapiens clone ccsbBroadEn_11001 NOTCH2 gene, encodes complete protein.
AK307843 - Homo sapiens cDNA, FLJ97791.
AL133036 - Homo sapiens mRNA; cDNA DKFZp434N181 (from clone DKFZp434N181).
JD073379 - Sequence 54403 from Patent EP1572962.
JD302428 - Sequence 283452 from Patent EP1572962.
AL049386 - Homo sapiens mRNA; cDNA DKFZp586M0918 (from clone DKFZp586M0918).
AK027869 - Homo sapiens cDNA FLJ14963 fis, clone PLACE4000522, weakly similar to NEUROGENIC LOCUS NOTCH PROTEIN.
JD312956 - Sequence 293980 from Patent EP1572962.
JD254428 - Sequence 235452 from Patent EP1572962.
JD045281 - Sequence 26305 from Patent EP1572962.
JD483686 - Sequence 464710 from Patent EP1572962.
JD167257 - Sequence 148281 from Patent EP1572962.
JD563945 - Sequence 544969 from Patent EP1572962.
JD236936 - Sequence 217960 from Patent EP1572962.
JD471245 - Sequence 452269 from Patent EP1572962.
JD515866 - Sequence 496890 from Patent EP1572962.
JD566752 - Sequence 547776 from Patent EP1572962.
JD322603 - Sequence 303627 from Patent EP1572962.
JD187906 - Sequence 168930 from Patent EP1572962.
JD321403 - Sequence 302427 from Patent EP1572962.
JD221482 - Sequence 202506 from Patent EP1572962.
JD221481 - Sequence 202505 from Patent EP1572962.
JD259598 - Sequence 240622 from Patent EP1572962.
JD236254 - Sequence 217278 from Patent EP1572962.
JD091327 - Sequence 72351 from Patent EP1572962.
JD359906 - Sequence 340930 from Patent EP1572962.
JD184675 - Sequence 165699 from Patent EP1572962.
JD437780 - Sequence 418804 from Patent EP1572962.
JD196921 - Sequence 177945 from Patent EP1572962.
JD211967 - Sequence 192991 from Patent EP1572962.
JD315345 - Sequence 296369 from Patent EP1572962.
JD556622 - Sequence 537646 from Patent EP1572962.
JD300421 - Sequence 281445 from Patent EP1572962.
JD349586 - Sequence 330610 from Patent EP1572962.
JD046729 - Sequence 27753 from Patent EP1572962.
JD259691 - Sequence 240715 from Patent EP1572962.
JD167437 - Sequence 148461 from Patent EP1572962.
JD146722 - Sequence 127746 from Patent EP1572962.
JD076087 - Sequence 57111 from Patent EP1572962.
JD044984 - Sequence 26008 from Patent EP1572962.
JD267368 - Sequence 248392 from Patent EP1572962.
JD252320 - Sequence 233344 from Patent EP1572962.
JD226301 - Sequence 207325 from Patent EP1572962.
JD194963 - Sequence 175987 from Patent EP1572962.
JD255067 - Sequence 236091 from Patent EP1572962.
JD130507 - Sequence 111531 from Patent EP1572962.
JD566730 - Sequence 547754 from Patent EP1572962.
JD551394 - Sequence 532418 from Patent EP1572962.
JD281571 - Sequence 262595 from Patent EP1572962.
JD485489 - Sequence 466513 from Patent EP1572962.
JD171281 - Sequence 152305 from Patent EP1572962.
JD204465 - Sequence 185489 from Patent EP1572962.
JD157895 - Sequence 138919 from Patent EP1572962.
JD255428 - Sequence 236452 from Patent EP1572962.
JD248512 - Sequence 229536 from Patent EP1572962.
JD548565 - Sequence 529589 from Patent EP1572962.
JD432722 - Sequence 413746 from Patent EP1572962.
JD552770 - Sequence 533794 from Patent EP1572962.
JD172806 - Sequence 153830 from Patent EP1572962.
JD204090 - Sequence 185114 from Patent EP1572962.
JD091719 - Sequence 72743 from Patent EP1572962.
JD251687 - Sequence 232711 from Patent EP1572962.
JD358218 - Sequence 339242 from Patent EP1572962.
JD353326 - Sequence 334350 from Patent EP1572962.
JD354496 - Sequence 335520 from Patent EP1572962.
DQ589480 - Homo sapiens piRNA piR-56592, complete sequence.
AX721311 - Sequence 271 from Patent WO0220754.
GQ231534 - Homo sapiens neurogenic locus notch-like protein 2 (NOTCH2) mRNA, complete cds.
DQ579629 - Homo sapiens piRNA piR-47741, complete sequence.
JD407350 - Sequence 388374 from Patent EP1572962.
JC506671 - Sequence 39 from Patent EP2733220.
JC737783 - Sequence 39 from Patent WO2014075939.
JD274087 - Sequence 255111 from Patent EP1572962.
JD436724 - Sequence 417748 from Patent EP1572962.
JD443842 - Sequence 424866 from Patent EP1572962.
JD341944 - Sequence 322968 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa04320 - Dorso-ventral axis formation
hsa04330 - Notch signaling pathway

BioCarta from NCI Cancer Genome Anatomy Project
h_hesPathway - Segmentation Clock

Reactome (by CSHL, EBI, and GO)

Protein Q04721 (Reactome details) participates in the following event(s):

R-HSA-157640 NEXT2 is cleaved to produce NICD2
R-HSA-157629 NOTCH2-ligand complex is cleaved to produce NEXT2
R-HSA-157933 NICD2 traffics to the nucleus
R-HSA-2197588 NICD2 binds RBPJ and MAML in the nucleus
R-HSA-1912349 Fucosylation of Pre-NOTCH by POFUT1
R-HSA-1980051 DLL4 binds NOTCH2
R-HSA-1980061 JAG2 binds NOTCH2
R-HSA-2220816 NOTCH2 binds CNTN1
R-HSA-2974737 NOTCH2 binds MDK
R-HSA-2976563 NOTCH2 coactivator complex and phosphorylated CREB1 bind GZMB promoter
R-HSA-2976716 NOTCH2 coactivator complex binds HES1 promoter
R-HSA-2976726 NOTCH2 coactivator complex binds HES5 promoter
R-HSA-2976742 NOTCH2 coactivator complex binds FCER2 promoter
R-HSA-212356 Formation of CSL-NICD coactivator complex
R-HSA-1912353 Glucosylation of Pre-NOTCH by POGLUT1
R-HSA-1912355 Glycosylation of Pre-NOTCH by FRINGE
R-HSA-1912369 NOTCH precursor cleaved to form mature NOTCH
R-HSA-1912378 Sialylation of Pre-NOTCH
R-HSA-1912352 Galactosylation of Pre-NOTCH
R-HSA-1912372 Fringe-modified Pre-NOTCH is cleaved by FURIN
R-HSA-1980048 DLL1 binds NOTCH2
R-HSA-1980056 JAG1 binds NOTCH2
R-HSA-2172172 Ubiquitination of DLL/JAG ligands upon binding to NOTCH2
R-HSA-1912408 Pre-NOTCH Transcription and Translation
R-HSA-157212 A third proteolytic cleavage releases NICD
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-156988 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor
R-HSA-157052 NICD traffics to nucleus
R-HSA-2197563 NOTCH2 intracellular domain regulates transcription
R-HSA-1912399 Pre-NOTCH Processing in the Endoplasmic Reticulum
R-HSA-1912422 Pre-NOTCH Expression and Processing
R-HSA-1980145 Signaling by NOTCH2
R-HSA-350054 Notch-HLH transcription pathway
R-HSA-1912420 Pre-NOTCH Processing in Golgi
R-HSA-5083630 Defective LFNG causes SCDO3
R-HSA-157118 Signaling by NOTCH
R-HSA-212436 Generic Transcription Pathway
R-HSA-3906995 Diseases associated with O-glycosylation of proteins
R-HSA-162582 Signal Transduction
R-HSA-73857 RNA Polymerase II Transcription
R-HSA-3781865 Diseases of glycosylation
R-HSA-74160 Gene expression (Transcription)
R-HSA-1643685 Disease

-  Other Names for This Gene
  Alternate Gene Symbols: ENST00000256646.1, ENST00000256646.2, ENST00000256646.3, ENST00000256646.4, ENST00000256646.5, ENST00000256646.6, NM_024408, NOTC2_HUMAN, Q04721, Q5T3X7, Q99734, Q9H240, uc001eik.1, uc001eik.2, uc001eik.3, uc001eik.4, uc001eik.5
UCSC ID: ENST00000256646.7
RefSeq Accession: NM_024408
Protein: Q04721 (aka NOTC2_HUMAN or NTC2_HUMAN)
CCDS: CCDS908.1

-  GeneReviews for This Gene
  GeneReviews article(s) related to gene NOTCH2:
alagille (Alagille Syndrome)

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.