Reactome: A Curated Pathway Database

Signaling by NOTCH2 (R-HSA-1980145)

Species Homo sapiens


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).

Locations in the PathwayBrowser
Additional Information
Compartment plasma membrane , cytosol , nucleoplasm
GO Biological Process Notch signaling pathway (0007219)
Literature References
pubMedId Title Journal Year
10958687 Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2 Mol Cell Biol 2000
10934472 Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2 Nat Cell Biol 2000
10551863 Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods J Biol Chem 1999
15569487 Function of Delta4 gene and its effects on 32D cell differentiation Chin Med J (Engl) 2004
20156974 ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo J Exp Med 2010
11518718 Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis J Biol Chem 2001
10206645 A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain Nature 1999
11187898 Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells Leukemia 2000
21632553 Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer Cancer Res. 2011
14567914 F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation Cell 2003
18469519 Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes Cell Cycle 2008
11986231 Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia Blood 2002
18724371 Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity Nat. Immunol. 2008
16773578 NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway Am J Hum Genet 2006
11866432 Functional diversity among Notch1, Notch2, and Notch3 receptors Biochem Biophys Res Commun 2002
11101851 MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors Nat Genet 2000
19379690 The canonical Notch signaling pathway: unfolding the activation mechanism Cell 2009
20816393 Canonical and non-canonical Notch ligands Curr Top Dev Biol 2010
20816392 Mechanistic insights into Notch receptor signaling from structural and biochemical studies Curr. Top. Dev. Biol. 2010
803282 Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur J. Pediatr. 1975
9207787 Mutations in the human Jagged1 gene are responsible for Alagille syndrome Nat. Genet. 1997
9207788 Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1 Nat. Genet. 1997
21378985 Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss Nat. Genet. 2011
21378989 Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis Nat. Genet. 2011
21681853 Mutations in NOTCH2 in families with Hajdu-Cheney syndrome Hum. Mutat. 2011