Notch signaling pathway (Bos taurus)

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ProteinNotch Signaling PathwayProtein - protein dissociationGATA3MAML1PTCRACDKN1ANOTCH1NOTCH2NOTCH4NOTCH3NOTCH1NOTCH2NOTCH4NOTCH3PMNUMAML2CCND1APH1BAPH1ANCSTNPSENENPSEN1PSEN2MAML3GSK3BRING1FHL1HDAC2HDAC1HEY1HES5EP300NCOR2NCOR1SPENSNW1DLL4DLL3DLL1JAG2JAG1ADAM17RBPJSAP30CIR1FBXW7CUL1SKP1ITCHNUMBTLE1NFKB1PIK3R2PIK3R1LCKMAGEA1AKT1AKT dependentgene expressionMYCMAPTJAK2STAT3HES6HES5HES1NUMBLDTX1HIF1ASRCPHEY2HES1HEY2HES1STAT3CYNUInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageReceptorProteinmRNALigandEnzyme complex


Description

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 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.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP61(78592) with a 98.0% conversion rate.

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Bibliography

  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

History

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CompareRevisionActionTimeUserComment
117573view11:22, 21 May 2021EweitzModified title
115960view08:26, 22 March 2021EgonwCopied the NetPath paper into the literature list
115950view07:13, 22 March 2021EgonwModified description
80867view15:29, 30 June 2015Mkutmonhomology conversion
67147view10:12, 26 June 2013Christine ChichesterOntology Term : 'Notch signaling pathway' added !
63356view22:22, 9 May 2013MaintBotUpdated to 2013 gpml schema
40530view19:30, 1 March 2011MaintBotRemoved redundant pathway information and comments
35713view23:19, 12 February 2010AlexanderPico
33772view00:06, 9 December 2009MaintBotAutomatic update of empty xrefs
32522view12:56, 17 August 2009MaintBotFixed text labels
31220view19:41, 13 August 2009MaintBotFixed text labels
30633view22:27, 29 July 2009MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADAM17ProteinENSBTAG00000001141 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6868
AKT1ProteinENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
APH1AProteinENSBTAG00000021482 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:51107
APH1BProteinENSBTAG00000010641 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:83464
CCND1RnaENSBTAG00000017514 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:595
CDKN1ARnaENSBTAG00000008353 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1026
CIR1ProteinENSBTAG00000038620 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9541
CUL1ProteinENSBTAG00000008736 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8454
DLL1ProteinENSBTAG00000031476 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:28514
DLL3ProteinENSBTAG00000010483 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10683
DLL4ProteinENSBTAG00000010361 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54567
DTX1ProteinENSBTAG00000016738 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1840
EP300ProteinENSBTAG00000016198 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2033
FBXW7ProteinENSBTAG00000007953 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55294
FHL1ProteinENSBTAG00000018513 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2273
GATA3RnaENSBTAG00000017243 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2625
GSK3BProteinENSBTAG00000048057 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2932
HDAC1ProteinENSBTAG00000012698 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3065
HDAC2ProteinENSBTAG00000011849 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3066
HES1ProteinENSBTAG00000000569 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3280
HES5ProteinENSBTAG00000002483 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:388585
HES6ProteinENSBTAG00000009870 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55502
HEY1RnaENSBTAG00000015717 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23462
HEY2ProteinENSBTAG00000000919 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23493
HIF1ARnaENSBTAG00000020935 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3091
ITCHProteinENSBTAG00000000308 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:83737
JAG1ProteinENSBTAG00000012817 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:182
JAG2ProteinENSBTAG00000007319 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3714
JAK2ProteinENSBTAG00000012047 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3717
LCKProteinENSBTAG00000012695 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3932
MAGEA1ProteinENSBTAG00000046045 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4100
MAML1ProteinENSBTAG00000047633 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9794
MAML2ProteinENSBTAG00000037962 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:84441
MAML3ProteinENSBTAG00000011373 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55534
MAPTProteinENSBTAG00000017512 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4137
MYCRnaENSBTAG00000008409 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4609
NCOR1ProteinENSBTAG00000013271 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9611
NCOR2ProteinENSBTAG00000024603 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9612
NCSTNProteinENSBTAG00000004334 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23385
NFKB1ProteinENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NOTCH1ProteinENSBTAG00000022799 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4851
NOTCH2ProteinENSBTAG00000007909 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4853
NOTCH3ProteinENSBTAG00000043971 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4854
NOTCH4ProteinENSBTAG00000025424 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4855
NUMBProteinENSBTAG00000011683 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8650
NUMBLProteinENSBTAG00000019461 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:9253
PIK3R1ProteinENSBTAG00000010989 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5295
PIK3R2ProteinHomologyConvert: Multiple homologues found: En:ENSBTAG00000002350;En:ENSBTAG00000002350;
PSEN1ProteinENSBTAG00000011757 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5663
PSEN2ProteinENSBTAG00000013197 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5664
PSENENProteinENSBTAG00000018593 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55851
PTCRARnaENSBTAG00000017097 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:171558
RBPJProteinENSBTAG00000003602 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3516
RING1ProteinENSBTAG00000018884 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6015
SAP30ProteinENSBTAG00000015578 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8819
SKP1ProteinENSBTAG00000025191 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6500
SNW1ProteinENSBTAG00000008136 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:22938
SPENProteinENSBTAG00000018729 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23013
SRCProteinENSBTAG00000008938 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6714
STAT3ProteinENSBTAG00000021523 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6774
TLE1ProteinENSBTAG00000000256 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7088

Annotated Interactions

No annotated interactions
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