ID:NOTC1_HUMAN DESCRIPTION: RecName: Full=Neurogenic locus notch homolog protein 1; Short=Notch 1; Short=hN1; AltName: Full=Translocation-associated notch protein TAN-1; Contains: RecName: Full=Notch 1 extracellular truncation; Contains: RecName: Full=Notch 1 intracellular domain; Short=NICD; 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. May be important for normal lymphocyte function. In altered form, may contribute to transformation or progression in some T-cell neoplasms. Involved in the maturation of both CD4+ and CD8+ cells in the thymus. May be important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, may function as a receptor for neuronal DNER and may be involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May enhance HIF1A function by sequestering HIF1AN away from HIF1A (By similarity). SUBUNIT: Heterodimer of a C-terminal fragment N(TM) and an N- terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1. The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (By similarity). INTERACTION: Q13526:PIN1; NbExp=9; IntAct=EBI-636374, EBI-714158; Q06330:RBPJ; NbExp=2; IntAct=EBI-636374, EBI-632552; Q13573:SNW1; NbExp=3; IntAct=EBI-636374, EBI-632715; SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein (By similarity). SUBCELLULAR LOCATION: Notch 1 intracellular domain: Nucleus (By similarity). Note=Following proteolytical processing NICD is translocated to the nucleus (By similarity). TISSUE SPECIFICITY: In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues. 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). Following endocytosis, 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: Phosphorylated (By similarity). PTM: O-glycosylated on the EGF-like domains. Contains both O- linked fucose and O-linked glucose. PTM: Ubiquitinated; undergoes 'Lys-29'-linked polyubiquitination catalyzed by ITCH. Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch. PTM: Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity). DISEASE: Defects in NOTCH1 are a cause of aortic valve disease 1 (AOVD1) [MIM:109730]. A common defect in the aortic valve in which two rather than three leaflets are present. It is often associated with aortic valve calcification and insufficiency. In extreme cases, the blood flow may be so restricted that the left ventricle fails to grow, resulting in hypoplastic left heart syndrome. SIMILARITY: Belongs to the NOTCH family. SIMILARITY: Contains 5 ANK repeats. SIMILARITY: Contains 36 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/NOTCH1ID30ch9q34.html";
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.
ModBase Predicted Comparative 3D Structure on P46531
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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.
BC046127 - Homo sapiens, clone IMAGE:4938771, mRNA. BC063597 - Homo sapiens cDNA clone IMAGE:4754960, partial cds. BC039147 - Homo sapiens Notch homolog 1, translocation-associated (Drosophila), mRNA (cDNA clone IMAGE:4746828), with apparent retained intron. AK000012 - Homo sapiens cDNA FLJ20005 fis, clone ADKA02526. BC049843 - Homo sapiens Notch homolog 1, translocation-associated (Drosophila), mRNA (cDNA clone IMAGE:4448593), with apparent retained intron. BC013208 - Homo sapiens Notch homolog 1, translocation-associated (Drosophila), mRNA (cDNA clone IMAGE:4156263). DI450742 - KR 1020140111673-A/11: COMBINATION THERAPY FOR TREATING HEARING AND BALANCE DISORDERS. HW767457 - JP 2014528704-A/11: Double-Stranded Oligonucleotide Compounds And Methods Of Use Thereof For Treating Hearing And Balance Disorders. JB837400 - Sequence 11 from Patent WO2013106494. JE566451 - Sequence 12 from Patent EP2853595. JE828145 - Sequence 12 from Patent WO2015043768. LF807178 - JP 2016528161-A/11: COMBINATION THERAPY FOR TREATING HEARING AND BALANCE DISORDERS. LZ947776 - JP 2016533190-A/12: NOTCH 1 specific siRNA molecules. AB209873 - Homo sapiens mRNA for notch1 preproprotein variant protein. JD038001 - Sequence 19025 from Patent EP1572962. JD120910 - Sequence 101934 from Patent EP1572962. JD129691 - Sequence 110715 from Patent EP1572962. JD389358 - Sequence 370382 from Patent EP1572962. JD271309 - Sequence 252333 from Patent EP1572962. JD230516 - Sequence 211540 from Patent EP1572962. JD144098 - Sequence 125122 from Patent EP1572962. JD561777 - Sequence 542801 from Patent EP1572962. CR457221 - Homo sapiens full open reading frame cDNA clone RZPDo834G108D for gene NOTCH1, Notch homolog 1, translocation-associated (Drosophila); complete cds, incl. stopcodon. JD158181 - Sequence 139205 from Patent EP1572962. JD227855 - Sequence 208879 from Patent EP1572962. JD280706 - Sequence 261730 from Patent EP1572962. JD094637 - Sequence 75661 from Patent EP1572962. JD436551 - Sequence 417575 from Patent EP1572962. JD062348 - Sequence 43372 from Patent EP1572962. JD396318 - Sequence 377342 from Patent EP1572962. JD365715 - Sequence 346739 from Patent EP1572962. JD348431 - Sequence 329455 from Patent EP1572962. JD239420 - Sequence 220444 from Patent EP1572962. JD089215 - Sequence 70239 from Patent EP1572962. JD339486 - Sequence 320510 from Patent EP1572962. JD171100 - Sequence 152124 from Patent EP1572962. CQ873737 - Sequence 156 from Patent WO2004076622. DD413574 - Regulation of Mammalian Cells. AF308602 - Homo sapiens NOTCH 1 (N1) mRNA, complete cds. M73980 - Human TAN-1 mRNA (homologue of Drosophila Notch gene), 5' end. DL491593 - Novel nucleic acids. DD356919 - Method of Screening for Compound Regulating Translation of Specific mRNA.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_hesPathway - Segmentation Clock h_ps1Pathway - Presenilin action in Notch and Wnt signaling h_notchpathway - Proteolysis and Signaling Pathway of Notch
Reactome (by CSHL, EBI, and GO)
Protein P46531 (Reactome details) participates in the following event(s):
R-HSA-157353 NEXT1 is cleaved to produce NICD1 R-HSA-157632 Complex of NOTCH1 with its ligand is cleaved to produce NEXT1 R-HSA-2666278 NOTCH1 t(7;9)(NOTCH1:M1580_K2555) is cleaved to produce NEXT1 R-HSA-2730752 NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding R-HSA-157926 NICD1 traffics to nucleus R-HSA-2220988 NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants R-HSA-1912388 NICD1 displaces co-repressor complex from RBPJ (CSL) R-HSA-1912396 NICD1 binds HIF1A R-NUL-2064264 NICD1 displaces NCOR co-repressor complex from CSL R-HSA-1912385 Phosphorylated NICD1 binds FBXW7 R-HSA-1912391 NICD1 is phosphorylated by CDK8 R-HSA-1912349 Fucosylation of Pre-NOTCH by POFUT1 R-HSA-1980042 NOTCH1 binds JAG1 R-HSA-1980044 NOTCH1 binds JAG2 R-HSA-1980122 DTX binds NOTCH1 R-HSA-1980128 NOTCH1 associates with negative regulators NUMB and ITCH R-HSA-1980130 NOTCH1 binds DLK1 R-HSA-1980138 NOTCH1 binds DLL/JAG ligand in cis R-NUL-2076711 rDll1 binds NOTCH1 in cis R-HSA-1912394 NICD1 in complex with RBPJ (CSL) recruits MAML 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-1852623 Ubiquitination of NICD1 by FBWX7 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-2220971 CDK8 phosphorylates NICD1 PEST domain mutants R-HSA-2220944 ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants R-HSA-2220976 NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding R-HSA-2769015 NICD1 PEST domain mutants translocate from cytosol to nucleus R-HSA-2220982 NICD1 PEST domain mutants displace co-repressor complex from RBPJ (CSL) R-HSA-1912386 Ubiquitination of NOTCH1 by ITCH in the absence of ligand R-HSA-373706 Contactin-1 (CNTN1) binds NOTCH1 R-HSA-1912398 NOTCH1 binds DNER R-HSA-1980123 DTX recruits beta-arrestin (ARRB) to NOTCH R-HSA-1980039 NOTCH1 binds DLL1 R-HSA-1980041 NOTCH1 binds DLL4 R-HSA-2691211 NOTCH1 HD domain mutants bind DLL4 R-HSA-2691214 NOTCH1 HD domain mutants bind JAG2 R-HSA-2691219 NOTCH1 HD domain mutants bind DLL1 R-HSA-2691226 NOTCH1 HD domain mutants bind JAG1 R-HSA-1912393 MAML in complex with NICD1 recruits CDK8 R-HSA-4396347 NOTCH1 Coactivator Complex binds HES1 promoter R-HSA-4396371 NOTCH1 Coactivator Complex binds MYC promoter R-HSA-4396379 NOTCH1 Coactivator Complex binds HES5 promoter R-HSA-4396382 NOTCH1 Coactivator Complex binds promoters of HEY genes R-HSA-8878220 RUNX3 binds the NOTCH1 coactivator complex R-HSA-9017835 NOTCH1 coactivator complex binds NOTCH3 gene R-HSA-2900743 NOTCH1 HD+PEST domain mutants bind JAG1 R-HSA-2900747 NOTCH1 HD+PEST domain mutants bind DLL4 R-HSA-2900748 NOTCH1 HD+PEST domain mutants bind DLL1 R-HSA-2900756 NOTCH1 HD+PEST domain mutants bind JAG2 R-HSA-2768993 NOTCH1 PEST domain mutants bind JAG2 R-HSA-2768999 NOTCH1 PEST domain mutants bind JAG1 R-HSA-2769000 NOTCH1 PEST domain mutants bind DLL4 R-HSA-2769008 NOTCH1 PEST domain mutants bind DLL1 R-HSA-2220964 NICD1 PEST domain mutants in complex with RBPJ (CSL) bind MAML R-HSA-1980074 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 R-HSA-8878237 RUNX3:NOTCH1 coactivator complex binds the HES1 gene promoter R-HSA-9021451 NOTCH1,NOTCH3 coactivator complex binds PLXND1 gene promoter R-HSA-2220957 NOTCH1 PEST domain mutants coactivator complex binds CDK8:CCNC R-HSA-4396392 NOTCH1 PEST domain mutants bind HES1 promoter R-HSA-4396393 NOTCH1 PEST domain mutants bind MYC promoter R-HSA-4396401 NOTCH1 PEST domain mutants bind HES5 promoter R-HSA-4396402 NOTCH1 PEST domain mutants bind promoters of HEY genes R-HSA-2737728 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD domain mutants R-HSA-2900765 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 HD+PEST domain mutants R-HSA-2769007 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 PEST domain mutants R-HSA-1912408 Pre-NOTCH Transcription and Translation R-HSA-157212 A third proteolytic cleavage releases NICD R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus R-HSA-156988 Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor R-HSA-2660826 Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant R-HSA-2691232 Constitutive Signaling by NOTCH1 HD Domain Mutants R-HSA-157052 NICD traffics to nucleus R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants R-HSA-2122947 NOTCH1 Intracellular Domain Regulates Transcription R-HSA-2644607 Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling R-HSA-1912399 Pre-NOTCH Processing in the Endoplasmic Reticulum R-HSA-1912422 Pre-NOTCH Expression and Processing R-HSA-1980143 Signaling by NOTCH1 R-HSA-2660825 Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant R-HSA-2691230 Signaling by NOTCH1 HD Domain Mutants in Cancer R-HSA-2644602 Signaling by NOTCH1 PEST Domain Mutants in Cancer R-HSA-2894858 Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer R-HSA-350054 Notch-HLH transcription pathway R-HSA-1912420 Pre-NOTCH Processing in Golgi R-HSA-5083630 Defective LFNG causes SCDO3 R-HSA-2644605 FBXW7 Mutants and NOTCH1 in Cancer R-HSA-157118 Signaling by NOTCH R-HSA-2644603 Signaling by NOTCH1 in Cancer R-HSA-8941856 RUNX3 regulates NOTCH signaling R-HSA-212436 Generic Transcription Pathway R-HSA-3906995 Diseases associated with O-glycosylation of proteins R-HSA-162582 Signal Transduction R-HSA-5663202 Diseases of signal transduction R-HSA-9013508 NOTCH3 Intracellular Domain Regulates Transcription R-HSA-8878159 Transcriptional regulation by RUNX3 R-HSA-73857 RNA Polymerase II Transcription R-HSA-3781865 Diseases of glycosylation R-HSA-1643685 Disease R-HSA-9012852 Signaling by NOTCH3 R-HSA-74160 Gene expression (Transcription)
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
