Signaling by NOTCH3 (Homo sapiens)

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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

External references

DataNodes

Name	Type	Database reference	Comment
14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) [extracellular region]	Protein	Q9UM47 (Uniprot-TrEMBL)
ADAM10 [plasma membrane]	Protein	O14672 (Uniprot-TrEMBL)
ADAM10:Zn++	Complex	REACT_3937 (Reactome)
APH1A [plasma membrane]	Protein	Q96BI3 (Uniprot-TrEMBL)
APH1B [plasma membrane]	Protein	Q8WW43 (Uniprot-TrEMBL)
DLL/JAG:NOTCH3	Complex	REACT_2798 (Reactome)
DLL/JAG	Protein	REACT_5356 (Reactome)
DLL1 [plasma membrane]	Protein	O00548 (Uniprot-TrEMBL)
DLL4 [plasma membrane]	Protein	Q9NR61 (Uniprot-TrEMBL)
JAG1 [plasma membrane]	Protein	P78504 (Uniprot-TrEMBL)
JAG2 [plasma membrane]	Protein	Q9Y219 (Uniprot-TrEMBL)
NCSTN [plasma membrane]	Protein	Q92542 (Uniprot-TrEMBL)
NEXT3	Protein	Q9UM47 (Uniprot-TrEMBL)
NICD3	Protein	Q9UM47 (Uniprot-TrEMBL)
NOTCH3 fragment:DLL/JAG	Complex	REACT_2424 (Reactome)
NOTCH3(1572-2321) [plasma membrane]	Protein	Q9UM47 (Uniprot-TrEMBL)
NOTCH3(1629-1661)	Protein	Q9UM47 (Uniprot-TrEMBL)
NOTCH3(40-1628) [extracellular region]	Protein	Q9UM47 (Uniprot-TrEMBL)
NOTCH3	Complex	REACT_4341 (Reactome)
PSEN2(1-297) [plasma membrane]	Protein	P49810 (Uniprot-TrEMBL)
PSENEN [plasma membrane]	Protein	Q9NZ42 (Uniprot-TrEMBL)
Pre-NOTCH Expression and Processing	Pathway	WP2786 (WikiPathways)	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+ [plasma membrane]	Metabolite	CHEBI:29105 (ChEBI)
gamma-secretase complex	Complex	REACT_5292 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
ADAM10:Zn++		mim-catalysis	REACT_1552 (Reactome)
	DLL/JAG:NOTCH3	Arrow	REACT_452 (Reactome)
DLL/JAG:NOTCH3			REACT_1552 (Reactome)
DLL/JAG			REACT_452 (Reactome)
	NEXT3	Arrow	REACT_1552 (Reactome)
NEXT3			REACT_1803 (Reactome)
	NICD3	Arrow	REACT_1135 (Reactome)
	NICD3	Arrow	REACT_1803 (Reactome)
NICD3			REACT_1135 (Reactome)
	NOTCH3 fragment:DLL/JAG	Arrow	REACT_1552 (Reactome)
	NOTCH3(1629-1661)	Arrow	REACT_1803 (Reactome)
NOTCH3			REACT_452 (Reactome)
			REACT_1135 (Reactome)	The cytosolic NICD3 translocates to the nucleus.
			REACT_1552 (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.
			REACT_1803 (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.
			REACT_452 (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.
gamma-secretase complex		mim-catalysis	REACT_1803 (Reactome)