Reactome | Signaling by NOTCH2

Signaling by NOTCH2

Stable Identifier

R-HSA-1980145

DOI

10.3180/REACT_118721.4

Type

Pathway

Species

Homo sapiens

Compartment

plasma membrane, cytosol, nucleoplasm

ReviewStatus

5/5

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NOTCH2 is activated by binding Delta-like and Jagged ligands (DLL/JAG) expressed in trans on neighboring cells (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). In trans ligand-receptor binding is followed by ADAM10 mediated (Gibb et al. 2010, Shimizu et al. 2000) and gamma secretase complex mediated cleavage of NOTCH2 (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 traffics to the nucleus where it acts as a transcriptional regulator. For a recent review of the cannonical NOTCH signaling, please refer to Kopan and Ilagan 2009, D'Souza et al. 2010, Kovall and Blacklow 2010. CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003) and MDK (midkine) (Huang et al. 2008, Gungor et al. 2011), which plays an important role in epithelial-to-mesenchymal transition, can also bind NOTCH2 and activate NOTCH2 signaling.

In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). The NICD2:RBPJ:MAML complex activates transcription from RBPJ binding promoter elements (RBEs) (Wu et al. 2000). NOTCH2 coactivator complexes directly stimulate transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets. NOTCH2 but not NOTCH1 coactivator complexes, stimulate FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development (Hubmann et al. 2002). NOTCH2 coactivator complexes together with CREBP1 and EP300 stimulate transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T cells (Maekawa et al. 2008).

NOTCH2 gene expression is differentially regulated during human B-cell development, with NOTCH2 transcripts appearing at late developmental stages (Bertrand et al. 2000).

NOTCH2 mutations are a rare cause of Alagille syndrome (AGS). AGS is a dominant congenital multisystem disorder characterized mainly by hepatic bile duct abnormalities. Craniofacial, heart and kidney abnormalities are also frequently observed in the Alagille spectrum (Alagille et al. 1975). AGS is predominantly caused by mutations in JAG1, a NOTCH2 ligand (Oda et al. 1997, Li et al. 1997), but it can also be caused by mutations in NOTCH2 (McDaniell et al. 2006).

Hajdu-Cheney syndrome, an autosomal dominant disorder characterized by severe and progressive bone loss, is caused by NOTCH2 mutations that result in premature C-terminal NOTCH2 truncation, probably leading to increased NOTCH2 signaling (Simpson et al. 2011, Isidor et al. 2011, Majewski et al. 2011).

Literature References

PubMed ID	Title	Journal	Year
10206645	A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain Wolfe, MS, Kopan, R, De Strooper, B, Schrijvers, V, Schroeter, EH, Cupers, P, Goate, A, Saftig, P, Craessaerts, K, Ray, WJ, Mumm, JS, Annaert, W	Nature	1999
18724371	Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity Saito, T, Sakata-Yanagimoto, M, Kurihara, T, Sone, S, Taniuchi, I, Kojima, H, Minato, Y, Kitamura, A, Ishifune, C, Yasutomo, K, Chiba, S, Yagita, H, Maekawa, Y	Nat. Immunol.	2008
10551863	Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods Yazaki, Y, Kanda, Y, Shimizu, K, Takahashi, T, Hirai, H, Kumano, K, Hamada, Y, Chiba, S, Hosoya, N	J Biol Chem	1999
21632553	Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer Izbicki, JR, Güngör, C, Kalinina, T, Vashist, YK, Bockhorn, M, Yekebas, E, Effenberger, KE, Zander, H	Cancer Res.	2011
803282	Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur Odièvre, M, Gautier, M, Alagille, D, Dommergues, JP	J. Pediatr.	1975
11866432	Functional diversity among Notch1, Notch2, and Notch3 receptors Shimizu, K, Hirai, H, Kumano, K, Hamada, Y, Saito, T, Chiba, S	Biochem Biophys Res Commun	2002
18469519	Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes Huang, Y, Wu, F, Sidransky, D, Ratovitski, EA, Trink, B, Hoque, MO	Cell Cycle	2008
9207787	Mutations in the human Jagged1 gene are responsible for Alagille syndrome Spinner, NB, Okajima, K, Meltzer, PS, Collins, FS, Genin, A, Oda, T, Chandrasekharappa, SC, Piccoli, DA, Elkahloun, AG, Krantz, ID, Pike, BL	Nat. Genet.	1997
11518718	Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis Saxena, MT, Kopan, R, Schroeter, EH, Mumm, JS	J Biol Chem	2001
20816392	Mechanistic insights into Notch receptor signaling from structural and biochemical studies Kovall, RA, Blacklow, SC	Curr. Top. Dev. Biol.	2010
10934472	Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2 Collazo, A, Johnston, SH, Hicks, C, Weinmaster, G, diSibio, G, Vogt, TF	Nat Cell Biol	2000
10958687	Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2 Kanda, Y, Kurokawa, M, Shimizu, K, Hirai, H, Kumano, K, Hamada, Y, Saito, T, Chiba, S, Hosoya, N	Mol Cell Biol	2000
15569487	Function of Delta4 gene and its effects on 32D cell differentiation Zhang, MH, Ji, CY, Zhao, JQ, Ma, DX, Cui, CS, Guo, NJ	Chin Med J (Engl)	2004
11986231	Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia Shehata, M, Berger, R, Schwarzmeier, JD, Duechler, M, Hilgarth, M, Hubmann, R, Dettke, M	Blood	2002
21378989	Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis Pichon, O, David, A, Isidor, B, Dina, C, Redon, R, Le Merrer, M, Jacquemont, S, Le Caignec, C, Faivre, L, Lindenbaum, P, Martin-Coignard, D, Mandel, JL, Cormier-Daire, V, Thauvin-Robinet, C, Bezieau, S	Nat. Genet.	2011
20156974	ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo Tew, JG, Gibb, DR, Rowe, WJ, Dempsey, PJ, Kang, DJ, Cichy, J, Conrad, DH, Crawford, HC, Yagita, H, El Sayed, R, El Shikh, M	J Exp Med	2010
21378985	Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss Burton, BK, Holder, SE, Kim, CA, Mansour, S, Irving, MD, Elmslie, FV, Drake, WM, Pauli, RM, Robertson, SP, Holder-Espinasse, M, Simpson, MA, Asilmaz, E, Stewart, H, Dafou, D, Trembath, RC, Aftimos, S, Brain, CE, Kim, KH, Gray, MJ	Nat. Genet.	2011
14567914	F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation Small, D, Cui, XY, Ling, EA, Hirai, H, Pallen, CJ, Okano, H, Karsak, M, Xiao, ZC, Maciag, T, Ang, BT, Takeda, Y, Watanabe, K, Duka, T, Ng, YK, Hu, QD, Nakafuku, M, Sankar, N, Aster, JC, Chiba, S, Kopan, R, Schachner, M, Trifonova, R, Chia, W, Hu, WP	Cell	2003
16773578	NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway Krantz, ID, Sanchez-Lara, PA, Spinner, NB, Pai, A, Warthen, DM, Piccoli, DA, McDaniell, R	Am J Hum Genet	2006
11187898	Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells Eckfeldt, CE, Bertrand, FE, LeBien, TW, Lysholm, AS	Leukemia	2000
20816393	Canonical and non-canonical Notch ligands D'Souza, B, Meloty-Kapella, L, Weinmaster, G	Curr Top Dev Biol	2010
11101851	MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors Blacklow, SC, Artavanis-Tsakonas, S, Aster, JC, Wu, L, Griffin, JD, Lake, R	Nat Genet	2000
19379690	The canonical Notch signaling pathway: unfolding the activation mechanism Kopan, R, Ilagan, MXG	Cell	2009
9207788	Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1 Genin, A, Kuo, WL, Li, L, Piccoli, DA, Hood, L, Banta, AB, Trask, BJ, Collins, CC, Rand, EB, Costa, T, Spinner, NB, Qi, M, Pierpont, ME, Krantz, ID, Deng, Y, Cochran, J	Nat. Genet.	1997
21681853	Mutations in NOTCH2 in families with Hajdu-Cheney syndrome Marcadier, J, Ste-Marie, LG, Caqueret, A, Boycott, KM, Patry, L, Marik, I, Schwartzentruber, JA, Majewski, J, Van Esch, H, Fryns, JP, McKiernan, FE	Hum. Mutat.	2011