Signaling by NOTCH3 (Homo sapiens)

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10, 25, 3210, 25, 312, 6, 22Signal receiving cellcytosolcytosolnucleoplasmSignal sending cellJAG1 ADAM10:Zn++DLL1 DLL/JAGPSENEN JAG1 APH1B ADAM10 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) NOTCH3(1572-2321) NICD3gamma-secretasecomplexJAG2 PSEN2(1-297) NOTCH3(40-1628) NOTCH3(1629-1661)JAG1 DLL/JAG:NOTCH3NOTCH3(1572-2321) Zn2+ DLL4 NOTCH3APH1A JAG2 DLL4 DLL1 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) NEXT3NOTCH3fragment:DLL/JAGNCSTN DLL1 Pre-NOTCH Expressionand ProcessingDLL4 JAG2 NICD31, 3-5, 7...


Description

Similar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH3, NICD3, into the cytosol. NICD3 subsequently traffics to the nucleus where it acts as a transcriptional regulator. View original pathway at:Reactome.

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Bibliography

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  1. Yamaguchi N, Oyama T, Ito E, Satoh H, Azuma S, Hayashi M, Shimizu K, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Ohwada S, Tatsuta K, Inoue J, Semba K, Watanabe S.; ''NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.''; PubMed Europe PMC Scholia
  2. Lin SE, Oyama T, Nagase T, Harigaya K, Kitagawa M.; ''Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling.''; PubMed Europe PMC Scholia
  3. Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMed Europe PMC Scholia
  4. Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M, Ciuffetta A, Colantoni S, Vacca A, Frati L, Gulino A, Felli MP, Screpanti I.; ''Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription.''; PubMed Europe PMC Scholia
  5. Rusanescu G, Mao J.; ''Notch3 is necessary for neuronal differentiation and maturation in the adult spinal cord.''; PubMed Europe PMC Scholia
  6. Claxton S, Fruttiger M.; ''Periodic Delta-like 4 expression in developing retinal arteries.''; PubMed Europe PMC Scholia
  7. Shimizu K, Chiba S, Saito T, Kumano K, Hamada Y, Hirai H.; ''Functional diversity among Notch1, Notch2, and Notch3 receptors.''; PubMed Europe PMC Scholia
  8. Zhang X, Liu X, Luo J, Xiao W, Ye X, Chen M, Li Y, Zhang GJ.; ''Notch3 inhibits epithelial-mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells.''; PubMed Europe PMC Scholia
  9. Irvin DK, Zurcher SD, Nguyen T, Weinmaster G, Kornblum HI.; ''Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development.''; PubMed Europe PMC Scholia
  10. Jung JG, Stoeck A, Guan B, Wu RC, Zhu H, Blackshaw S, Shih IeM, Wang TL.; ''Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer.''; PubMed Europe PMC Scholia
  11. Wang W, Prince CZ, Mou Y, Pollman MJ.; ''Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.''; PubMed Europe PMC Scholia
  12. Ohashi S, Natsuizaka M, Naganuma S, Kagawa S, Kimura S, Itoh H, Kalman RA, Nakagawa M, Darling DS, Basu D, Gimotty PA, Klein-Szanto AJ, Diehl JA, Herlyn M, Nakagawa H.; ''A NOTCH3-mediated squamous cell differentiation program limits expansion of EMT-competent cells that express the ZEB transcription factors.''; PubMed Europe PMC Scholia
  13. Park JT, Li M, Nakayama K, Mao TL, Davidson B, Zhang Z, Kurman RJ, Eberhart CG, Shih IeM, Wang TL.; ''Notch3 gene amplification in ovarian cancer.''; PubMed Europe PMC Scholia
  14. Storkebaum E, Quaegebeur A, Vikkula M, Carmeliet P.; ''Cerebrovascular disorders: molecular insights and therapeutic opportunities.''; PubMed Europe PMC Scholia
  15. Groot AJ, Habets R, Yahyanejad S, Hodin CM, Reiss K, Saftig P, Theys J, Vooijs M.; ''Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins.''; PubMed Europe PMC Scholia
  16. Maier MM, Gessler M.; ''Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.''; PubMed Europe PMC Scholia
  17. Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling HJ, Hayday AC, Frati L, von Boehmer H, Gulino A, Screpanti I.; ''Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis.''; PubMed Europe PMC Scholia
  18. Dang L, Yoon K, Wang M, Gaiano N.; ''Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon.''; PubMed Europe PMC Scholia
  19. Indraccolo S, Minuzzo S, Masiero M, Pusceddu I, Persano L, Moserle L, Reboldi A, Favaro E, Mecarozzi M, Di Mario G, Screpanti I, Ponzoni M, Doglioni C, Amadori A.; ''Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy.''; PubMed Europe PMC Scholia
  20. Gray GE, Mann RS, Mitsiadis E, Henrique D, Carcangiu ML, Banks A, Leiman J, Ward D, Ish-Horowitz D, Artavanis-Tsakonas S.; ''Human ligands of the Notch receptor.''; PubMed Europe PMC Scholia
  21. Bellavia D, Checquolo S, Campese AF, Felli MP, Gulino A, Screpanti I.; ''Notch3: from subtle structural differences to functional diversity.''; PubMed Europe PMC Scholia
  22. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, Ter Brugge PJ, Jonkers J, Slingerland J, Minn AJ.; ''Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways.''; PubMed Europe PMC Scholia
  23. Liu L, Chen X, Wang Y, Qu Z, Lu Q, Zhao J, Yan X, Zhang H, Zhou Y.; ''Notch3 is important for TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancer bone metastasis by regulating ZEB-1.''; PubMed Europe PMC Scholia
  24. Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T.; ''Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.''; PubMed Europe PMC Scholia
  25. Krebs LT, Xue Y, Norton CR, Sundberg JP, Beatus P, Lendahl U, Joutel A, Gridley T.; ''Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation.''; PubMed Europe PMC Scholia
  26. Rehman M, Gurrapu S, Cagnoni G, Capparuccia L, Tamagnone L.; ''PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells.''; PubMed Europe PMC Scholia
  27. Arasada RR, Amann JM, Rahman MA, Huppert SS, Carbone DP.; ''EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling.''; PubMed Europe PMC Scholia
  28. Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman ES, Hayday AC, Lendahl U, Frati L, Gulino A, Screpanti I.; ''Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice.''; PubMed Europe PMC Scholia
  29. Chen X, Thiaville MM, Chen L, Stoeck A, Xuan J, Gao M, Shih IeM, Wang TL.; ''Defining NOTCH3 target genes in ovarian cancer.''; PubMed Europe PMC Scholia
  30. Park JT, Shih IeM, Wang TL.; ''Identification of Pbx1, a potential oncogene, as a Notch3 target gene in ovarian cancer.''; PubMed Europe PMC Scholia
  31. Matsumoto A, Onoyama I, Sunabori T, Kageyama R, Okano H, Nakayama KI.; ''Fbxw7-dependent degradation of Notch is required for control of "stemness" and neuronal-glial differentiation in neural stem cells.''; PubMed Europe PMC Scholia
  32. Faux CH, Turnley AM, Epa R, Cappai R, Bartlett PF.; ''Interactions between fibroblast growth factors and Notch regulate neuronal differentiation.''; PubMed Europe PMC Scholia
  33. Rauen T, Raffetseder U, Frye BC, Djudjaj S, Mühlenberg PJ, Eitner F, Lendahl U, Bernhagen J, Dooley S, Mertens PR.; ''YB-1 acts as a ligand for Notch-3 receptors and modulates receptor activation.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114804view16:30, 25 January 2021ReactomeTeamReactome version 75
113248view11:31, 2 November 2020ReactomeTeamReactome version 74
112466view15:41, 9 October 2020ReactomeTeamReactome version 73
101375view11:26, 1 November 2018ReactomeTeamreactome version 66
100913view21:01, 31 October 2018ReactomeTeamreactome version 65
100454view19:36, 31 October 2018ReactomeTeamreactome version 64
100001view16:19, 31 October 2018ReactomeTeamreactome version 63
99001view15:17, 22 October 2018DeSlchanged reactome ID number, since old number no longer exists.
93913view13:44, 16 August 2017ReactomeTeamreactome version 61
93489view11:25, 9 August 2017ReactomeTeamreactome version 61
87182view19:57, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86585view09:21, 11 July 2016ReactomeTeamreactome version 56
83126view10:02, 18 November 2015ReactomeTeamVersion54
81466view13:00, 21 August 2015ReactomeTeamVersion53
76939view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76644view12:01, 16 July 2014ReactomeTeamFixed remaining interactions
75974view10:03, 11 June 2014ReactomeTeamRe-fixing comment source
75677view11:00, 10 June 2014ReactomeTeamReactome 48 Update
75032view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74676view08:44, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) ProteinQ9UM47 (Uniprot-TrEMBL)
ADAM10 ProteinO14672 (Uniprot-TrEMBL)
ADAM10:Zn++ComplexR-HSA-157186 (Reactome)
APH1A ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B ProteinQ8WW43 (Uniprot-TrEMBL)
DLL/JAG:NOTCH3ComplexR-HSA-157638 (Reactome)
DLL/JAGComplexR-HSA-157643 (Reactome)
DLL1 ProteinO00548 (Uniprot-TrEMBL)
DLL4 ProteinQ9NR61 (Uniprot-TrEMBL)
JAG1 ProteinP78504 (Uniprot-TrEMBL)
JAG2 ProteinQ9Y219 (Uniprot-TrEMBL)
NCSTN ProteinQ92542 (Uniprot-TrEMBL)
NEXT3ProteinQ9UM47 (Uniprot-TrEMBL)
NICD3ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH3 fragment:DLL/JAGComplexR-HSA-157650 (Reactome)
NOTCH3(1572-2321) ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH3(1629-1661)ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH3(40-1628) ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH3ComplexR-HSA-157048 (Reactome)
PSEN2(1-297) ProteinP49810 (Uniprot-TrEMBL)
PSENEN ProteinQ9NZ42 (Uniprot-TrEMBL)
Pre-NOTCH Expression and ProcessingPathwayR-HSA-1912422 (Reactome) In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009).

The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011).

In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling.
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexR-HSA-157343 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADAM10:Zn++mim-catalysisR-HSA-157626 (Reactome)
DLL/JAG:NOTCH3ArrowR-HSA-157644 (Reactome)
DLL/JAG:NOTCH3R-HSA-157626 (Reactome)
DLL/JAGR-HSA-157644 (Reactome)
NEXT3ArrowR-HSA-157626 (Reactome)
NEXT3R-HSA-157659 (Reactome)
NICD3ArrowR-HSA-157659 (Reactome)
NICD3ArrowR-HSA-157937 (Reactome)
NICD3R-HSA-157937 (Reactome)
NOTCH3 fragment:DLL/JAGArrowR-HSA-157626 (Reactome)
NOTCH3(1629-1661)ArrowR-HSA-157659 (Reactome)
NOTCH3R-HSA-157644 (Reactome)
R-HSA-157626 (Reactome) Ligand binding induces a conformational change in the NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and results in cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3. The extracellular NOTCH3 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
R-HSA-157644 (Reactome) The NOTCH3 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell.
R-HSA-157659 (Reactome) NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD3 into the cytosol.
R-HSA-157937 (Reactome) The cytosolic NICD3 translocates to the nucleus.
gamma-secretase complexmim-catalysisR-HSA-157659 (Reactome)
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