Notch signaling (WP61)

Homo sapiens

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.


Akhilesh Pandey , Kristina Hanspers , NetPath , Denise Slenter , Lauren J. Dupuis , Egon Willighagen , and Eric Weitz


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Homo sapiens




Pathway Ontology

Notch signaling pathway


Label Type Compact URI Comment
MTOR GeneProduct hgnc.symbol:MTOR
MAML1 Protein ncbigene:9794
NOTCH1 Protein ncbigene:4851
NOTCH2 Protein ncbigene:4853
NOTCH4 Protein ncbigene:4855
NOTCH3 Protein ncbigene:4854
NOTCH1 Protein ncbigene:4851
NOTCH2 Protein ncbigene:4853
NOTCH4 Protein ncbigene:4855
NOTCH3 Protein ncbigene:4854
MAML2 Protein ncbigene:84441
APH1B Protein ncbigene:83464
APH1A Protein ncbigene:51107
NCSTN Protein ncbigene:23385
PSENEN Protein ncbigene:55851
PSEN2 Protein ncbigene:5663
PSEN1 Protein ncbigene:5664
MAML3 Protein ncbigene:55534
GSK3B Protein ncbigene:2932
RING1 Protein ncbigene:6015
FHL1 Protein ncbigene:2273
HDAC2 Protein ncbigene:3066
HDAC1 Protein ncbigene:3065
EP300 Protein ncbigene:2033
NCOR2 Protein ncbigene:9612
NCOR1 Protein ncbigene:9611
SPEN Protein ncbigene:23013
SNW1 Protein ncbigene:22938
DLL4 Protein ncbigene:54567
DLL3 Protein ncbigene:10683
DLL1 Protein ncbigene:28514
JAG2 Protein ncbigene:3714
JAG1 Protein ncbigene:182
ADAM17 Protein ncbigene:6868
RBPJ Protein ncbigene:3516
SAP30 Protein ncbigene:8819
CIR Protein ncbigene:9541
FBXW7 Protein ncbigene:55294
CUL1 Protein ncbigene:8454
SKP1 Protein ncbigene:6500
ITCH Protein ncbigene:83737
NUMB Protein ncbigene:8650
TLE1 Protein ncbigene:7088
NFKB1 Protein ncbigene:4790
PIK3R2 Protein ncbigene:5296
PIK3R1 Protein ncbigene:5295
LCK Protein ncbigene:3932
MAGEA1 Protein ncbigene:4100
AKT1 Protein ncbigene:207
JAK2 Protein ncbigene:3717
STAT3 Protein ncbigene:6774
HES6 Protein ncbigene:55502
HES5 Protein ncbigene:388585
HES1 Protein ncbigene:3280
NUMBL Protein ncbigene:9253
DTX1 Protein ncbigene:1840
SRC Protein ncbigene:6714
HEY2 Protein ncbigene:23493
HEY1 Protein ncbigene:3280
STAT3 Protein ncbigene:6774


  1. NetPath: a public resource of curated signal transduction pathways. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. Genome Biol. 2010 Jan 12;11(1):R3. PubMed Europe PMC Scholia