Signaling by NOTCH4 (Homo sapiens)

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1, 2, 4-12, 14...7203, 14, 2642010, 14, 21, 26cytosolcytosolSignal receiving cellSignal sending cellnucleoplasmPSME3 MAMLD1 MAML2 UBC(229-304) PSMD14 PSMA3 p-4S-NICD4:YWHAZdimerUBC(153-228) p-S423,S425-SMAD3ACTA2 gene12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) RPS27A(1-76) PSMB8 NOTCH4 coactivatorcomplexNICD4 YWHAZ p-4S-NICD4PSMB5 ADAM10:Zn2+PSMA1 MAML1 UBC(457-532) CREBBP NICD4:TACC3gamma-secretasecomplexPSMB9 YWHAZ NICD1 PSMD13 NICD4NOTCH4(1337-2003) PSMD5 APH1A PolyUb-p-NICD4PSMC1 UbHES1PSME1 MAML3 NOTCH4(1337-2003) UBB(153-228) NEXT4PSMD12 SKP1 RBPJ YWHAZ dimerNICD4 UBC(381-456) NOTCH4(1337-2003) PSMB3 NICD4 MAML3 PSMA2 MAML3 PSMC6 PSMB10 PSMB4 RBX1 p-S423,S425-SMAD3 MAMLDLL4:NOTCH4NCSTN UBC(1-76) PSMA5 PSMC2 FLT4APH1B p-NICD4RBPJ CUL1 PSMD4 NOTCH4JAG1 HEY1 geneHEY2MAML2 FBXW7alpha NOTCH4 coactivatorcomplex:FLT4 genePSMB1 NICD4 PSMD9 PSMD8 PSMC5 MAML1 UBC(305-380) HEY1ADPADAM10 JAG1:NOTCH4PSEN1(1-298) UBC(77-152) TACC3NICD4Unknown proteinkinaseUBB(1-76) PSME2 26S proteasomePSEN1(299-467) KAT2B FLT4 gene12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) MAML1 MAML3 p-4S-NICD4 DLL4:NOTCH4,JAG1:NOTCH4DLL4HES5 geneZn2+ RBPJ MAML2 ACTA2PSMD2 HES5RBPJUBB(77-152) JAG1 KAT2A p-T308,S473-AKT1PSEN2(298-448) 12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) UBA52(1-76) NOTCH4(1432-1466)MAMLD1 NICD4:p-S423,S425-SMAD3PSMB7 MAML2 UBC(533-608) NOTCH4(1337-2003) PSMD1 FBXW7gamma PSMA4 DLL4 PSMB6 PSMB2 MAMLD1 PSMD3 SHFM1 NICD2 HES1 genePSMD11 FLT4 gene PSMC4 MAML1 PSMA6 HEY2 geneNOTCH1,NOTCH2,NOTCH4coactivator complexPSMF1 PSMA7 TACC3 12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) JAG1PSMD10 PSMD6 NICD4 DLL4 PSENEN FBXW7:SKP1:CUL1:RBX1PSMD7 PSEN2(1-297) EP300 SNW1 MAMLD1 UBC(609-684) PSMC3 ATP13, 2331, 333129


The NOTCH4 gene locus was discovered as a frequent site of insertion for the proviral genome of the mouse mammary tumor virus (MMTV) (Gallahan and Callahan 1987). MMTV-insertion results in aberrant expression of the mouse mammary tumor gene int-3, which was subsequently discovered to represent the intracellular domain of Notch4 (Robbins et al. 1992, Uyttendaele et al. 1996).

NOTCH4 is prevalently expressed in endothelial cells (Uyttendaele et al. 1996). DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells (Shawber et al. 2003, Shawber et al. 2007), but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested (Aste-Amezaga et al. 2010, James et al. 2014). The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4) (Saxena et al. 2001, Das et al. 2004). NICD4 traffics to the nucleus where it acts as a transcription factor and stimulates expression of NOTCH target genes HES1, HES5, HEY1 and HEY2, as well as VEGFR3 and ACTA2 (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Shawber et al. 2007, Tang et al. 2008, Bargo et al. 2010). NOTCH4 signaling can be downregulated by AKT1 phosphorylation-induced cytoplasmic retention (Ramakrishnan et al. 2015) as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination (Wu et al. 2001, Tsunematsu et al. 2004).

NOTCH4 was reported to inhibit NOTCH1 signaling in-cis, by binding to NOTCH1 and interfering with the S1 cleavage of NOTCH1, thus preventing production of functional NOTCH1 heterodimers at the cell surface (James et al. 2014).

NOTCH4 is involved in development of the vascular system. Overexpression of constitutively active Notch4 in mouse embryonic vasculature results in abnormal vessel structure and patterning (Uyttendaele et al. 2001). NOTCH4 may act to inhibit apoptosis of endothelial cells (MacKenzie et al. 2004).

Expression of int-3 interferes with normal mammary gland development in mice and promotes tumorigenesis. The phenotype of mice expressing int-3 in mammary glands is dependent on the presence of Rbpj (Raafat et al. 2009). JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with elevated expression of NOTCH target genes HES1, HEY1 and HEY2, and is associated with increased population of breast cancer stem cells and distant metastases (Simoes et al. 2015). Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling (Raafat et al. 2006) and on int-3-induced activaton of NFKB signaling (Raafat et al. 2017). In head and neck squamous cell carcinoma (HNSCC), high NOTCH4 expression correlates with elevated HEY1 levels, increased cell proliferation and survival, epithelial-to-mesenchymal transition (EMT) phenotype and cisplatin resistance (Fukusumi et al. 2018). In melanoma, however, exogenous NOTCH4 expression correlates with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016). NOTCH4 is frequently overexpressed in gastric cancer. Increased NOTCH4 levels correlate with activation of WNT signaling and gastric cancer progression (Qian et al. 2015).

NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation (Lai et al. 2013).

During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner (Li et al. 2015). NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4 (Kusano and Raab-Traub 2001). View original pathway at Reactome.


Pathway is converted from Reactome ID: 9013694
Reactome version: 75
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Reactome Author: Jassal, Bijay

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  1. Raafat A, Bargo S, McCurdy D, Callahan R.; ''The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis.''; PubMed Europe PMC Scholia
  2. Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, Chawengsaksophak K, Rossant J, Accili D, Skobe M, Kitajewski J.; ''Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression.''; PubMed Europe PMC Scholia
  3. Bargo S, Raafat A, McCurdy D, Amirjazil I, Shu Y, Traicoff J, Plant J, Vonderhaar BK, Callahan R.; ''Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats.''; PubMed Europe PMC Scholia
  4. Raafat A, Bargo S, Anver MR, Callahan R.; ''Mammary development and tumorigenesis in mice expressing a truncated human Notch4/Int3 intracellular domain (h-Int3sh).''; PubMed Europe PMC Scholia
  5. Raafat A, Zoltan-Jones A, Strizzi L, Bargo S, Kimura K, Salomon D, Callahan R.; ''Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis.''; PubMed Europe PMC Scholia
  6. Qian C, Liu F, Ye B, Zhang X, Liang Y, Yao J.; ''Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling.''; PubMed Europe PMC Scholia
  7. Tang Y, Urs S, Liaw L.; ''Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site.''; PubMed Europe PMC Scholia
  8. James AC, Szot JO, Iyer K, Major JA, Pursglove SE, Chapman G, Dunwoodie SL.; ''Notch4 reveals a novel mechanism regulating Notch signal transduction.''; PubMed Europe PMC Scholia
  9. Kusano S, Raab-Traub N.; ''An Epstein-Barr virus protein interacts with Notch.''; PubMed Europe PMC Scholia
  10. Fukusumi T, Guo TW, Sakai A, Ando M, Ren S, Haft S, Liu C, Amornphimoltham P, Gutkind JS, Califano JA.; ''The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma.''; PubMed Europe PMC Scholia
  11. Li Y, Wu S, Pu J, Huang X, Zhang P.; ''Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-β signalling pathway.''; PubMed Europe PMC Scholia
  12. Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J.; ''Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene.''; PubMed Europe PMC Scholia
  13. Welcker M, Clurman BE.; ''FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.''; PubMed Europe PMC Scholia
  14. Bonyadi Rad E, Hammerlindl H, Wels C, Popper U, Ravindran Menon D, Breiteneder H, Kitzwoegerer M, Hafner C, Herlyn M, Bergler H, Schaider H.; ''Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors.''; PubMed Europe PMC Scholia
  15. Aste-Amézaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE.; ''Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors.''; PubMed Europe PMC Scholia
  16. MacKenzie F, Duriez P, Wong F, Noseda M, Karsan A.; ''Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways.''; PubMed Europe PMC Scholia
  17. Shawber CJ, Das I, Francisco E, Kitajewski J.; ''Notch signaling in primary endothelial cells.''; PubMed Europe PMC Scholia
  18. Das I, Craig C, Funahashi Y, Jung KM, Kim TW, Byers R, Weng AP, Kutok JL, Aster JC, Kitajewski J.; ''Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function.''; PubMed Europe PMC Scholia
  19. Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J.; ''SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.''; PubMed Europe PMC Scholia
  20. Ramakrishnan G, Davaakhuu G, Chung WC, Zhu H, Rana A, Filipovic A, Green AR, Atfi A, Pannuti A, Miele L, Tzivion G.; ''AKT and 14-3-3 regulate Notch4 nuclear localization.''; PubMed Europe PMC Scholia
  21. Tsunematsu R, Nakayama K, Oike Y, Nishiyama M, Ishida N, Hatakeyama S, Bessho Y, Kageyama R, Suda T, Nakayama KI.; ''Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development.''; PubMed Europe PMC Scholia
  22. Gallahan D, Callahan R.; ''Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors.''; PubMed Europe PMC Scholia
  23. Strohmaier H, Spruck CH, Kaiser P, Won KA, Sangfelt O, Reed SI.; ''Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line.''; PubMed Europe PMC Scholia
  24. Lai PY, Tsai CB, Tseng MJ.; ''Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes.''; PubMed Europe PMC Scholia
  25. Saxena MT, Schroeter EH, Mumm JS, Kopan R.; ''Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.''; PubMed Europe PMC Scholia
  26. Simões BM, O'Brien CS, Eyre R, Silva A, Yu L, Sarmiento-Castro A, Alférez DG, Spence K, Santiago-Gómez A, Chemi F, Acar A, Gandhi A, Howell A, Brennan K, Rydén L, Catalano S, Andó S, Gee J, Ucar A, Sims AH, Marangoni E, Farnie G, Landberg G, Howell SJ, Clarke RB.; ''Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.''; PubMed Europe PMC Scholia
  27. Robbins J, Blondel BJ, Gallahan D, Callahan R.; ''Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells.''; PubMed Europe PMC Scholia
  28. Uyttendaele H, Ho J, Rossant J, Kitajewski J.; ''Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium.''; PubMed Europe PMC Scholia
  29. Andersson ER, Lendahl U.; ''Therapeutic modulation of Notch signalling--are we there yet?''; PubMed Europe PMC Scholia
  30. Raafat A, Lawson S, Bargo S, Klauzinska M, Strizzi L, Goldhar AS, Buono K, Salomon D, Vonderhaar BK, Callahan R.; ''Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis.''; PubMed Europe PMC Scholia
  31. Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMed Europe PMC Scholia
  32. 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
  33. Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMed Europe PMC Scholia


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101242view11:13, 1 November 2018ReactomeTeamreactome version 66
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99024view15:31, 24 October 2018DeSlchanged reactome ID number, since old number no longer exists.
93915view13:44, 16 August 2017ReactomeTeamreactome version 61
93491view11:25, 9 August 2017ReactomeTeamreactome version 61
87181view19:56, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
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81465view13:00, 21 August 2015ReactomeTeamVersion53
76938view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76643view12:01, 16 July 2014ReactomeTeamFixed remaining interactions
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75676view11:00, 10 June 2014ReactomeTeamReactome 48 Update
75031view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74675view08:44, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) ProteinQ99466 (Uniprot-TrEMBL)
26S proteasomeComplexR-HSA-177750 (Reactome)
ACTA2 geneGeneProductENSG00000107796 (Ensembl)
ACTA2ProteinP62736 (Uniprot-TrEMBL)
ADAM10 ProteinO14672 (Uniprot-TrEMBL)
ADAM10:Zn2+ComplexR-HSA-157186 (Reactome)
ADPMetaboliteCHEBI:456216 (ChEBI)
APH1A ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B ProteinQ8WW43 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
DLL4 ProteinQ9NR61 (Uniprot-TrEMBL)
DLL4:NOTCH4,JAG1:NOTCH4ComplexR-HSA-9604269 (Reactome)
DLL4:NOTCH4ComplexR-HSA-2105041 (Reactome)
DLL4ProteinQ9NR61 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
FBXW7:SKP1:CUL1:RBX1ComplexR-HSA-1604469 (Reactome)
FBXW7alpha ProteinQ969H0-1 (Uniprot-TrEMBL)
FBXW7gamma ProteinQ969H0-4 (Uniprot-TrEMBL)
FLT4 gene ProteinENSG00000037280 (Ensembl)
FLT4 geneGeneProductENSG00000037280 (Ensembl)
FLT4ProteinP35916 (Uniprot-TrEMBL)
HES1 geneGeneProductENSG00000114315 (Ensembl)
HES1ProteinQ14469 (Uniprot-TrEMBL)
HES5 geneGeneProductENSG00000197921 (Ensembl)
HES5ProteinQ5TA89 (Uniprot-TrEMBL)
HEY1 geneGeneProductENSG00000164683 (Ensembl)
HEY1ProteinQ9Y5J3 (Uniprot-TrEMBL)
HEY2 geneGeneProductENSG00000135547 (Ensembl)
HEY2ProteinQ9UBP5 (Uniprot-TrEMBL)
JAG1 ProteinP78504 (Uniprot-TrEMBL)
JAG1:NOTCH4ComplexR-HSA-9604245 (Reactome)
JAG1ProteinP78504 (Uniprot-TrEMBL)
KAT2A ProteinQ92830 (Uniprot-TrEMBL)
KAT2B ProteinQ92831 (Uniprot-TrEMBL)
MAML1 ProteinQ92585 (Uniprot-TrEMBL)
MAML2 ProteinQ8IZL2 (Uniprot-TrEMBL)
MAML3 ProteinQ96JK9 (Uniprot-TrEMBL)
MAMLD1 ProteinQ13495 (Uniprot-TrEMBL)
MAMLComplexR-HSA-212357 (Reactome)
NCSTN ProteinQ92542 (Uniprot-TrEMBL)
NEXT4ProteinQ99466 (Uniprot-TrEMBL)
NICD1 ProteinP46531 (Uniprot-TrEMBL)
NICD2 ProteinQ04721 (Uniprot-TrEMBL)
NICD4 ProteinQ99466 (Uniprot-TrEMBL)
NICD4:TACC3ComplexR-HSA-9604678 (Reactome)
NICD4:p-S423,S425-SMAD3ComplexR-HSA-9605420 (Reactome)
NICD4ProteinQ99466 (Uniprot-TrEMBL)
NOTCH1,NOTCH2,NOTCH4 coactivator complexComplexR-HSA-9604665 (Reactome)
NOTCH4 coactivator complex:FLT4 geneComplexR-HSA-9604465 (Reactome)
NOTCH4 coactivator complexComplexR-HSA-9013697 (Reactome)
NOTCH4(1337-2003) ProteinQ99466 (Uniprot-TrEMBL)
NOTCH4(1432-1466)ProteinQ99466 (Uniprot-TrEMBL)
NOTCH4ComplexR-HSA-157053 (Reactome)
PSEN1(1-298) ProteinP49768 (Uniprot-TrEMBL)
PSEN1(299-467) ProteinP49768 (Uniprot-TrEMBL)
PSEN2(1-297) ProteinP49810 (Uniprot-TrEMBL)
PSEN2(298-448) ProteinP49810 (Uniprot-TrEMBL)
PSENEN ProteinQ9NZ42 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PolyUb-p-NICD4ProteinQ99466 (Uniprot-TrEMBL)
RBPJ ProteinQ06330 (Uniprot-TrEMBL)
RBPJProteinQ06330 (Uniprot-TrEMBL)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SNW1 ProteinQ13573 (Uniprot-TrEMBL)
TACC3 ProteinQ9Y6A5 (Uniprot-TrEMBL)
TACC3ProteinQ9Y6A5 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-68524 (Reactome)
Unknown protein kinaseR-HSA-9604605 (Reactome)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
YWHAZ dimerComplexR-HSA-206751 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexR-HSA-157343 (Reactome)
p-4S-NICD4 ProteinQ99466 (Uniprot-TrEMBL)
p-4S-NICD4:YWHAZ dimerComplexR-HSA-9604390 (Reactome)
p-4S-NICD4ProteinQ99466 (Uniprot-TrEMBL)
p-NICD4ProteinQ99466 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-S423,S425-SMAD3ProteinP84022 (Uniprot-TrEMBL)
p-T308,S473-AKT1ProteinP31749 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-9604642 (Reactome)
ACTA2 geneR-HSA-9604664 (Reactome)
ACTA2ArrowR-HSA-9604664 (Reactome)
ADAM10:Zn2+mim-catalysisR-HSA-9604264 (Reactome)
ADPArrowR-HSA-9604328 (Reactome)
ATPR-HSA-9604328 (Reactome)
DLL4:NOTCH4,JAG1:NOTCH4R-HSA-9604264 (Reactome)
DLL4:NOTCH4ArrowR-HSA-2168987 (Reactome)
DLL4R-HSA-2168987 (Reactome)
FBXW7:SKP1:CUL1:RBX1mim-catalysisR-HSA-9604629 (Reactome)
FLT4 geneR-HSA-9604451 (Reactome)
FLT4 geneR-HSA-9604471 (Reactome)
FLT4ArrowR-HSA-9604471 (Reactome)
HES1 geneR-HSA-9013711 (Reactome)
HES1ArrowR-HSA-9013711 (Reactome)
HES5 geneR-HSA-9604446 (Reactome)
HES5ArrowR-HSA-9604446 (Reactome)
HEY1 geneR-HSA-9604550 (Reactome)
HEY1ArrowR-HSA-9604550 (Reactome)
HEY2 geneR-HSA-9604553 (Reactome)
HEY2ArrowR-HSA-9604553 (Reactome)
JAG1:NOTCH4ArrowR-HSA-9604247 (Reactome)
JAG1R-HSA-9604247 (Reactome)
MAMLR-HSA-9013693 (Reactome)
NEXT4ArrowR-HSA-9604264 (Reactome)
NEXT4R-HSA-9604294 (Reactome)
NICD4:TACC3ArrowR-HSA-9604675 (Reactome)
NICD4:p-S423,S425-SMAD3ArrowR-HSA-9605414 (Reactome)
NICD4ArrowR-HSA-9604294 (Reactome)
NICD4ArrowR-HSA-9604308 (Reactome)
NICD4R-HSA-9013693 (Reactome)
NICD4R-HSA-9604308 (Reactome)
NICD4R-HSA-9604328 (Reactome)
NICD4R-HSA-9604606 (Reactome)
NICD4R-HSA-9604675 (Reactome)
NICD4R-HSA-9605414 (Reactome)
NOTCH1,NOTCH2,NOTCH4 coactivator complexArrowR-HSA-9604664 (Reactome)
NOTCH4 coactivator complex:FLT4 geneArrowR-HSA-9604451 (Reactome)
NOTCH4 coactivator complex:FLT4 geneArrowR-HSA-9604471 (Reactome)
NOTCH4 coactivator complexArrowR-HSA-9013693 (Reactome)
NOTCH4 coactivator complexArrowR-HSA-9013711 (Reactome)
NOTCH4 coactivator complexArrowR-HSA-9604446 (Reactome)
NOTCH4 coactivator complexArrowR-HSA-9604550 (Reactome)
NOTCH4 coactivator complexArrowR-HSA-9604553 (Reactome)
NOTCH4 coactivator complexR-HSA-9604451 (Reactome)
NOTCH4(1432-1466)ArrowR-HSA-9604294 (Reactome)
NOTCH4R-HSA-2168987 (Reactome)
NOTCH4R-HSA-9604247 (Reactome)
PolyUb-p-NICD4ArrowR-HSA-9604629 (Reactome)
PolyUb-p-NICD4R-HSA-9604642 (Reactome)
R-HSA-2168987 (Reactome) Both DLL4 and NOTCH4 are strongly expressed in the vascular endothelium and DLL4 is able to activate NOTCH4 signaling (Shutter et al. 2000, Shawber et al. 2003, Shawber et al. 2007). In mice, Notch4 and Dll4 are specifically expressed in arterial endothelial cells, and Dll4 is required for normal arterial patterning and development (Duarte et al. 2004).
R-HSA-9013693 (Reactome) In the nucleus, NICD4 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind) proteins MAML1, MAML2 or MAML3 (possibly also MAMLD1). NICD4:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (Lin et al. 2002).

Besides NICD4, RBPJ and MAML, NOTCH4 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD4, it is not shown here. More details are available in the pathway Signaling by NOTCH1.

NOTCH4 does not alter DNA binding specificity of RBPJ (Del Bianco et al. 2010).
R-HSA-9013711 (Reactome) NOTCH4 expression correlates with increased HES1 gene transcription in different cell types (Raafat et al. 2004, Lai et al. 2013, Simoes et al. 2015). A recombinant human NICD4 stimulates transcription from the recombinant human HES1-luciferase reporter construct (Raafat et al. 2004).
R-HSA-9604247 (Reactome) JAG1 can activate NOTCH4 signaling, based on co-culture of JAG1-expressing and NOTCH4 expressing HUVEC cells (human umbilical vein endothelial cell line) (Shawber et al. 2007). JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with an increase in population of breast cancer stem cells (Simoes et al. 2015).
R-HSA-9604264 (Reactome) Based on sequence similarity with other NOTCH family members and the requirement for knockout of both Notch1 and Notch4 in endothelial cells to recapitulate vasculature defects seen upon endothelial cell-specific Adam10 knockout, it is plausible that ADAM10 cleaves ligand-activated NOTCH4, releasing the membrane-bound NEXT4 fragment (Alabi et al. 2016).
R-HSA-9604294 (Reactome) NEXT4 fragment of NOTCH4 is further cleaved at the S3 site by the gamma-secretase complex, which releases the intracellular domain NICD4 into the cytosol (Saxena et al. 2001, Das et al. 2004).
R-HSA-9604308 (Reactome) The cytosolic NICD4 translocates to the nucleus. Trafficking of NICD4 to the nucleus is negatively regulated by binding of NICD4 to 14-3-3-zeta (YWHAZ), which happens upon NICD4 phosphorylation by activated AKT1 (Ramakrishnan et al. 2015).
R-HSA-9604328 (Reactome) Recombinant human AKT1 phosphorylates recombinant human NICD4 on four AKT-target sites conserved in primates: S1495, S1847, S1865 and S1917 (Ramakrishnan et al. 2015).
R-HSA-9604387 (Reactome) AKT1-mediated phosphorylation of NOTCH4 intracellular domain fragment NICD4 leads to binding of NICD4 to 14-3-3-zeta (YWHAZ). Binding to YWHAZ sequesters NICD4 to the cytosol, preventing its trafficking to the nucleus, and thus negatively regulates NOTCH4 signaling (Ramakrishnan et al. 2015).
R-HSA-9604446 (Reactome) The NOTCH4 co-activator complex, composed of NICD4 (NOTCH4 intracellular domain), RBPJ (CSL) and one of mastermind proteins, MAML1, MAML2 or MAML3, stimulates transcription from the HES5 gene promoter. The highest level of transcriptional activation of HES5 by NOTCH4 is seen when MAML2 is overexpressed, compared to the other two MAML proteins (Lin et al. 2002).
R-HSA-9604451 (Reactome) The NOTCH4 coactivator complex, composed of NICD4 (NOTCH4 intracellular domain fragment), RBPJ (CSL) and one of mastermind proteins, MAML1, MAML2 or MAML3, binds to CSL response elements in the promoter of the FLT4 (VEGFR3) gene, encoding Vascular endothelial growth factor receptor-3 (Shawber et al. 2007).
R-HSA-9604471 (Reactome) Transcription of the FLT4 (VEGFR3) gene, encoding Vascular endothelial growth factor receptor-3, is directly stimulated by the NOTCH4 co-activator complex (Shawber et al. 2007).
R-HSA-9604550 (Reactome) Increased NOTCH4 levels correlate with increased HEY1 gene expression (Tsunematsu et al. 2004, Simoes et al. 2015, Bonyadi Rad et al. 2016, Fukusumi et al. 2018). NOTCH4-mediated upregulation of HEY1 in head and neck squamous cell carcinoma (HNSCC) is associated with epithelial-to-mesenchymal transition (EMT) phenotype (Fukusumi et al. 2018). In melanoma, however, HEY1 and HEY2 expression downstream of NOTCH4 is associated with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016).
R-HSA-9604553 (Reactome) Increased NOTCH4 levels and activity correlate with increased HEY2 gene expression (Bargo et al. 2010, Simoes et al. 2015, Bonyadi Rad et al. 2016).
R-HSA-9604606 (Reactome) Unknown protein kinase phosphorylates the C-terminus of NICD4 (NOTCH4 intracellular domain fragment) (Wu et al. 2001).
R-HSA-9604629 (Reactome) The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4 (NOTCH4 intracellular domain fragment), targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004). Notch4 level also increases when Fbxw7 is downregulated by RNA in mouse embryonic fibroblasts (Mao et al. 2004).
R-HSA-9604642 (Reactome) FBXW7-mediated ubiquitination targets NICD4 (NOTCH4 intracellular domain fragment) for proteasome-mediated degradation (Wu et al. 2001).
R-HSA-9604664 (Reactome) ACTA2 gene, encoding smooth muscle alpha actin, possesses several RBPJ (CSL) response elements in its promoter region. Transcription of ACTA2 is positively regulated by NOTCH1, NOTCH2 and NOTCH4 (Tang et al. 2008).
R-HSA-9604675 (Reactome) Based on studies in mice, the intracellular domain of NOTCH4, NICD4, binds to transforming acidic coiled-coil protein-3 (TACC3). TACC3 is implicated as a negative regulator of NOTCH4 signaling and may compete with NICD4 binding to RBPJ (Bargo et al. 2010).
R-HSA-9605414 (Reactome) NOTCH4 intracellular domain fragment (NICD4) binds phosphorylated SMAD3 upon activation of TGF-beta signaling. (Sun et al. 2005, Grabias and Konstantopoulos 2013). NICD4 may also bind SMAD2 and SMAD4 (Sun et al. 2005). NICD4 promotes ubiquitination and proteasome-mediated degradation of SMAD3 through and unknown mechanism (Grabias and Konstantopoulos 2013) and inhibits transcription mediated by the heterotrimer of SMAD3, SMAD2 and SMAD4, thus negatively regulating TGF-beta signaling (Sun et al. 2005, Grabias and Konstantopoulos 2013).
RBPJR-HSA-9013693 (Reactome)
TACC3R-HSA-9604675 (Reactome)
UbArrowR-HSA-9604642 (Reactome)
UbR-HSA-9604629 (Reactome)
Unknown protein kinasemim-catalysisR-HSA-9604606 (Reactome)
YWHAZ dimerR-HSA-9604387 (Reactome)
gamma-secretase complexmim-catalysisR-HSA-9604294 (Reactome)
p-4S-NICD4:YWHAZ dimerArrowR-HSA-9604387 (Reactome)
p-4S-NICD4:YWHAZ dimerTBarR-HSA-9604308 (Reactome)
p-4S-NICD4ArrowR-HSA-9604328 (Reactome)
p-4S-NICD4R-HSA-9604387 (Reactome)
p-NICD4ArrowR-HSA-9604606 (Reactome)
p-NICD4R-HSA-9604629 (Reactome)
p-S423,S425-SMAD3R-HSA-9605414 (Reactome)
p-T308,S473-AKT1mim-catalysisR-HSA-9604328 (Reactome)
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