Notch signaling pathway (Homo sapiens)

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Protein1Notch signaling pathwayProtein - protein dissociationGATA3CDKN1AMAML1PTCRANOTCH1NOTCH2NOTCH4NOTCH3NOTCH1NOTCH2NOTCH4NOTCH3PMNUMAML2CCND1APH1BAPH1ANCSTNPSENENPSEN2PSEN1MAML3GSK3BRING1FHL1HDAC2HDAC1HEY1HES5EP300NCOR2NCOR1SPENSNW1DLL4DLL3DLL1JAG2JAG1ADAM17RBPJSAP30CIRFBXW7CUL1SKP1ITCHNUMBTLE1NFKB1PIK3R2PIK3R1LCKMAGEA1AKT1AKT dependentgene expressionMYCMTORJAK2STAT3HES6HES5HES1NUMBLDTX1HIF1ASRCPHEY2HES1HEY2HEY1STAT3CYNUInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLegendPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageReceptorProteinmRNALigandEnzyme complex


The Notch pathway is an evolutionally conserved signaling pathway which plays an important role in diverse developmental and physiological processes. These include cell-fate determination, tissue patterning and morphogenesis, cell differentiation, proliferation and cell death. The Notch pathway is named after the Drosophila mutants that showed irregular notches of missing tissue at the insect wing blade tips. The Notch gene was cloned in 1985. Proteins of the Notch families are single-pass transmembrane proteins that function both as cell surface receptors and nuclear transcriptional regulators. Four Notch receptors (Notch 1-4) have been identified in mammals. Mature Notch receptors are non-covalent heterodimers consisting of an extracellular subunit (NEC) and a transmembrane subunit (NTM). NEC possess multiple EGF-like repeats and three specialized Lin-Notch repeats (LNR) that forms a tight hydrophobic interaction with extracellular stump of NTM. This region masks an A disintegrin and metalloprotease (ADAM) cleavage site. The region where these two subunits interact is called the heterodimerization domain (HD). Notch ligands are also transmembrane proteins with multiple EGF-like repeats, a short cytoplasmic tail and a specialized delta-serrate-lag2 (DSL) domain at the N-terminus. There are five canonical Notch ligands i.e. Jagged (JAG1 and JAG2), Delta-like (DLL1, DLL3, DLL4) in mammals. Notch signaling activation occurs upon ligand-receptor binding, which are expressed on two adjacent cells. Ligand binding causes dissociation of NEC from NTM, unmasking the ADAM cleavage site. The NEC fragment is trans- endocytosed into the ligand expressing cells. The full-length receptor minus the NEC fragment is cleaved at the membrane by ADAM17 generating an intermediate, Notch extracellular truncation (NEXT). This is further cleaved by γ-secretase that generates an active Notch intracellular fragment (NIC) or Notch intracellular domain (NICD). The γ-secretase complex is composed of PSEN1, PSEN2, PSENEN, NCSTN and APH1 (A or B). Following these two cleavage steps, the NICD is released into the cytoplasm and translocates into the nucleus to regulate transcription of Notch target genes. Upon translocation into the nucleus, NICD binds to RBPJ which is a constitutive repressor of Notch signaling. RBPJ represses Notch target gene expression by recruiting a co-repressor complex, which includes NCOR1, NCOR2, SNW1, CIR, HDAC1, HDAC2, SPEN and FHL1 and SAP30. NICD binding to RBPJ replaces the co-repressor complex with a co-activator complex which includes MAML1-3, EP300 and SNW1. Primary Notch target genes include two families of transcriptional factors Hes, including HES1 and HES5 as well as Hey including HEY1 and HEY2. Other Notch target genes include CCND1, CDKN1A, GATA3 and PTCRA. CNTN1 acts as a functional ligand of Notch. This trans-extracellular interaction causes γ-secretase-dependent nuclear translocation of the NICD. This signaling is involved in oligodendrocyte precursor cell differentiation and upregulation of myelin-related protein MAG. In addition to the canonical Notch pathway, there is increasing evidence showing RBPJ independent non-canonical pathways. been fully characterized. Physical interaction of NOTCH-1IC with LCK- PI3K may mediate non-nuclear cross-talk with AKT, leading to survival signaling. Notch stimulation through AKT pathway leads to down regulation of MYC expression. Activation of SRC/STAT3 pathway by Notch signaling is dependent on the expression of Notch effector HES1 transcription factor. The induction of HES1 enhanced SRC phosphorylation. This activated SRC kinase was found to be responsible for the enhanced phosphorylation of STAT3. The HES1 and HES5 proteins associate with and facilitate the complex formation between JAK2 and STAT3, thus promoting STAT3 phosphorylation and activation. The activated STAT3 translocates from the cytoplasm to the nucleus and induces transcriptional activation of target gene expression (including HIF1A).

Please access this pathway at NetSlim database.

If you use this pathway, please cite following paper:

Kandasamy, K., Mohan, S. S., Raju, R., Keerthikumar, S., Kumar, G. S. S., Venugopal, A. K., Telikicherla, D., Navarro, J. D., Mathivanan, S., Pecquet, C., Gollapudi, S. K., Tattikota, S. G., Mohan, S., Padhukasahasram, H., Subbannayya, Y., Goel, R., Jacob, H. K. C., Zhong, J., Sekhar, R., Nanjappa, V., Balakrishnan, L., Subbaiah, R., Ramachandra, Y. L., Rahiman, B. A., Prasad, T. S. K., Lin, J., Houtman, J. C. D., Desiderio, S., Renauld, J., Constantinescu, S. N., Ohara, O., Hirano, T., Kubo, M., Singh, S., Khatri, P., Draghici, S., Bader, G. D., Sander, C., Leonard, W. J. and Pandey, A. (2010). NetPath: A public resource of curated signal transduction pathways. Genome Biology. 11:R3.

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  1. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GS, Venugopal AK, Telikicherla D, Navarro JD, Mathivanan S, Pecquet C, Gollapudi SK, Tattikota SG, Mohan S, Padhukasahasram H, Subbannayya Y, Goel R, Jacob HK, Zhong J, Sekhar R, Nanjappa V, Balakrishnan L, Subbaiah R, Ramachandra YL, Rahiman BA, Prasad TS, Lin JX, Houtman JC, Desiderio S, Renauld JC, Constantinescu SN, Ohara O, Hirano T, Kubo M, Singh S, Khatri P, Draghici S, Bader GD, Sander C, Leonard WJ, Pandey A; ''NetPath: a public resource of curated signal transduction pathways.''; Genome Biol, 2010 PubMed Europe PMC Scholia


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115833view20:38, 17 March 2021EgonwCopied the NetPath paper into the bibliography
115831view20:18, 17 March 2021EgonwModified description
108322view20:55, 6 December 2019L DupuisConverted interactions to graphical lines in legend
107434view06:51, 8 October 2019DeSlModified title
105486view05:43, 8 August 2019KhanspersModified description
105469view05:16, 8 August 2019KhanspersModified description
78592view14:51, 7 January 2015MaintBotadded missing graphIds
70097view18:41, 12 July 2013MaintBotupdating to 2013 schema
47972view14:20, 23 April 2012NetPathModified description
45344view20:24, 7 October 2011KhanspersOntology Term : 'Notch signaling pathway' added !
44599view21:06, 21 September 2011KhanspersAdded category
44598view21:04, 21 September 2011KhanspersModified description
44597view21:03, 21 September 2011KhanspersUpdating content to NetSlim
44114view20:40, 24 August 2011KhanspersReverted to version '23:22, 1 March 2011' by Khanspers
44037view23:23, 22 August 2011KhanspersModified description
44036view23:20, 22 August 2011KhanspersUpdating pathway from NetSlim
41109view23:22, 1 March 2011MaintBotRemoved redundant pathway information and comments
35651view21:42, 12 February 2010KhanspersModified description
20805view11:29, 14 November 2008MaintBot[[Pathway:Homo sapiens:Delta-Notch NetPath 3]] moved to [[Pathway:WP61]]: Moved to stable identifier
7984view13:46, 7 January 2008MaintBot[[Pathway:Human:Delta-Notch NetPath 3]] moved to [[Pathway:Homo sapiens:Delta-Notch NetPath 3]]: Renaming species
7616view16:04, 18 December 2007MaintBotfixed category names
7212view12:33, 4 November 2007MaintBotAdded categories to GPML
6308view22:17, 22 May 2007A.Pandeygpml file for [[Human:Delta-Notch_NetPath_3]]

External references


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NameTypeDatabase referenceComment
ADAM17Protein6868 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
APH1AProtein51107 (Entrez Gene)
APH1BProtein83464 (Entrez Gene)
CCND1Rna595 (Entrez Gene)
CDKN1ARna1026 (Entrez Gene)
CIRProtein9541 (Entrez Gene)
CUL1Protein8454 (Entrez Gene)
DLL1Protein28514 (Entrez Gene)
DLL3Protein10683 (Entrez Gene)
DLL4Protein54567 (Entrez Gene)
DTX1Protein1840 (Entrez Gene)
EP300Protein2033 (Entrez Gene)
FBXW7Protein55294 (Entrez Gene)
FHL1Protein2273 (Entrez Gene)
GATA3Rna2625 (Entrez Gene)
GSK3BProtein2932 (Entrez Gene)
HDAC1Protein3065 (Entrez Gene)
HDAC2Protein3066 (Entrez Gene)
HES1Rna3280 (Entrez Gene)
HES5Protein388585 (Entrez Gene)
HES6Protein55502 (Entrez Gene)
HEY1Rna23462 (Entrez Gene)
HEY1Protein3280 (Entrez Gene)
HEY2Protein23493 (Entrez Gene)
HIF1ARna3091 (Entrez Gene)
ITCHProtein83737 (Entrez Gene)
JAG1Protein182 (Entrez Gene)
JAG2Protein3714 (Entrez Gene)
JAK2Protein3717 (Entrez Gene)
LCKProtein3932 (Entrez Gene)
MAGEA1Protein4100 (Entrez Gene)
MAML1Protein9794 (Entrez Gene)
MAML2Protein84441 (Entrez Gene)
MAML3Protein55534 (Entrez Gene)
MTORProtein4137 (Entrez Gene)
MYCRna4609 (Entrez Gene)
NCOR1Protein9611 (Entrez Gene)
NCOR2Protein9612 (Entrez Gene)
NCSTNProtein23385 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
NOTCH1Protein4851 (Entrez Gene)
NOTCH2Protein4853 (Entrez Gene)
NOTCH3Protein4854 (Entrez Gene)
NOTCH4Protein4855 (Entrez Gene)
NUMBProtein8650 (Entrez Gene)
NUMBLProtein9253 (Entrez Gene)
PIK3R1Protein5295 (Entrez Gene)
PIK3R2Protein5296 (Entrez Gene)
PSEN1Protein5664 (Entrez Gene)
PSEN2Protein5663 (Entrez Gene)
PSENENProtein55851 (Entrez Gene)
PTCRARna171558 (Entrez Gene)
RBPJProtein3516 (Entrez Gene)
RING1Protein6015 (Entrez Gene)
SAP30Protein8819 (Entrez Gene)
SKP1Protein6500 (Entrez Gene)
SNW1Protein22938 (Entrez Gene)
SPENProtein23013 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
STAT3Protein6774 (Entrez Gene)
TLE1Protein7088 (Entrez Gene)

Annotated Interactions

No annotated interactions

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