Notch signaling pathway (WP1064)

Bos taurus

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 [http://www.netpath.org/netslim/notch_pathway.html NetSlim] database. If you use this pathway, please cite the 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.

Authors

Alex Pico , Christine Chichester , Martina Summer-Kutmon , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

Notch signaling pathway

Participants

Label Type Compact URI Comment
MAML1 Protein ensembl:ENSBTAG00000047633 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9794
NOTCH1 Protein ensembl:ENSBTAG00000022799 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4851
NOTCH2 Protein ensembl:ENSBTAG00000007909 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4853
NOTCH4 Protein ensembl:ENSBTAG00000025424 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4855
NOTCH3 Protein ensembl:ENSBTAG00000043971 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4854
MAML2 Protein ensembl:ENSBTAG00000037962 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:84441
APH1B Protein ensembl:ENSBTAG00000010641 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:83464
APH1A Protein ensembl:ENSBTAG00000021482 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51107
NCSTN Protein ensembl:ENSBTAG00000004334 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23385
PSENEN Protein ensembl:ENSBTAG00000018593 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55851
PSEN1 Protein ensembl:ENSBTAG00000011757 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5663
PSEN2 Protein ensembl:ENSBTAG00000013197 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5664
MAML3 Protein ensembl:ENSBTAG00000011373 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55534
GSK3B Protein ensembl:ENSBTAG00000048057 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2932
RING1 Protein ensembl:ENSBTAG00000018884 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6015
FHL1 Protein ensembl:ENSBTAG00000018513 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2273
HDAC2 Protein ensembl:ENSBTAG00000011849 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3066
HDAC1 Protein ensembl:ENSBTAG00000012698 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3065
EP300 Protein ensembl:ENSBTAG00000016198 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2033
NCOR2 Protein ensembl:ENSBTAG00000024603 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9612
NCOR1 Protein ensembl:ENSBTAG00000013271 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9611
SPEN Protein ensembl:ENSBTAG00000018729 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23013
SNW1 Protein ensembl:ENSBTAG00000008136 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:22938
DLL4 Protein ensembl:ENSBTAG00000010361 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54567
DLL3 Protein ensembl:ENSBTAG00000010483 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10683
DLL1 Protein ensembl:ENSBTAG00000031476 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:28514
JAG2 Protein ensembl:ENSBTAG00000007319 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3714
JAG1 Protein ensembl:ENSBTAG00000012817 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:182
ADAM17 Protein ensembl:ENSBTAG00000001141 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6868
RBPJ Protein ensembl:ENSBTAG00000003602 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3516
SAP30 Protein ensembl:ENSBTAG00000015578 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8819
CIR1 Protein ensembl:ENSBTAG00000038620 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9541
FBXW7 Protein ensembl:ENSBTAG00000007953 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55294
CUL1 Protein ensembl:ENSBTAG00000008736 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8454
SKP1 Protein ensembl:ENSBTAG00000025191 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6500
ITCH Protein ensembl:ENSBTAG00000000308 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:83737
NUMB Protein ensembl:ENSBTAG00000011683 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8650
TLE1 Protein ensembl:ENSBTAG00000000256 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7088
NFKB1 Protein ensembl:ENSBTAG00000020270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
PIK3R1 Protein ensembl:ENSBTAG00000010989 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
LCK Protein ensembl:ENSBTAG00000012695 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3932
MAGEA1 Protein ensembl:ENSBTAG00000046045 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4100
AKT1 Protein ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
MAPT Protein ensembl:ENSBTAG00000017512 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4137
JAK2 Protein ensembl:ENSBTAG00000012047 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3717
STAT3 Protein ensembl:ENSBTAG00000021523 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6774
HES6 Protein ensembl:ENSBTAG00000009870 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55502
HES5 Protein ensembl:ENSBTAG00000002483 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:388585
HES1 Protein ensembl:ENSBTAG00000000569 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3280
NUMBL Protein ensembl:ENSBTAG00000019461 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9253
DTX1 Protein ensembl:ENSBTAG00000016738 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1840
SRC Protein ensembl:ENSBTAG00000008938 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
HEY2 Protein ensembl:ENSBTAG00000000919 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23493

References

  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