Signaling by NOTCH4 (Homo sapiens)

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Bibliography

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

History

External references

DataNodes

Name	Type	Database reference	Comment
12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336)	Protein	Q99466 (Uniprot-TrEMBL)
ADAM10	Protein	O14672 (Uniprot-TrEMBL)
ADAM10:Zn++	Complex	R-HSA-157186 (Reactome)
APH1A	Protein	Q96BI3 (Uniprot-TrEMBL)
APH1B	Protein	Q8WW43 (Uniprot-TrEMBL)
DLL/JAG:NOTCH4	Complex	R-HSA-157653 (Reactome)
DLL/JAG	Complex	R-HSA-157643 (Reactome)
DLL1	Protein	O00548 (Uniprot-TrEMBL)
DLL4	Protein	Q9NR61 (Uniprot-TrEMBL)
JAG1	Protein	P78504 (Uniprot-TrEMBL)
JAG2	Protein	Q9Y219 (Uniprot-TrEMBL)
NCSTN	Protein	Q92542 (Uniprot-TrEMBL)
NEXT4	Protein	Q99466 (Uniprot-TrEMBL)
NICD4	Protein	Q99466 (Uniprot-TrEMBL)
NOTCH4 fragment:DLL/JAG	Complex	R-HSA-157627 (Reactome)
NOTCH4(1337-2003)	Protein	Q99466 (Uniprot-TrEMBL)
NOTCH4(1432-1466)	Protein	Q99466 (Uniprot-TrEMBL)
NOTCH4(24-1431)	Protein	Q99466 (Uniprot-TrEMBL)
NOTCH4	Complex	R-HSA-157053 (Reactome)
PSEN2(1-297)	Protein	P49810 (Uniprot-TrEMBL)
PSENEN	Protein	Q9NZ42 (Uniprot-TrEMBL)
Pre-NOTCH Expression and Processing	Pathway	R-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+	Metabolite	CHEBI:29105 (ChEBI)
gamma-secretase complex	Complex	R-HSA-157343 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
ADAM10:Zn++		mim-catalysis	R-HSA-157649 (Reactome)
	DLL/JAG:NOTCH4	Arrow	R-HSA-157633 (Reactome)
DLL/JAG:NOTCH4			R-HSA-157649 (Reactome)
DLL/JAG			R-HSA-157633 (Reactome)
	NEXT4	Arrow	R-HSA-157649 (Reactome)
NEXT4			R-HSA-157648 (Reactome)
	NICD4	Arrow	R-HSA-157648 (Reactome)
	NICD4	Arrow	R-HSA-157941 (Reactome)
NICD4			R-HSA-157941 (Reactome)
	NOTCH4 fragment:DLL/JAG	Arrow	R-HSA-157649 (Reactome)
	NOTCH4(1432-1466)	Arrow	R-HSA-157648 (Reactome)
NOTCH4			R-HSA-157633 (Reactome)
			R-HSA-157633 (Reactome)	The NOTCH4 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell.
			R-HSA-157648 (Reactome)	NEXT4 fragment of NOTCH4 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD4 into the cytosol.
			R-HSA-157649 (Reactome)	Ligand binding induces a conformational change in the NOTCH4, probably through mechanical pulling of NOTCH4 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH4 and results in cleavage of NOTCH4 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH4 fragment NEXT4. The extracellular NOTCH4 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
			R-HSA-157941 (Reactome)	The cytosolic NICD4 translocates to the nucleus.
gamma-secretase complex		mim-catalysis	R-HSA-157648 (Reactome)