Signaling by NOTCH2 (Homo sapiens)
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Description
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). View original pathway at:Reactome.
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). View original pathway at:Reactome.
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coactivator
complex:p-S133-CREB1:EP300:GZMB GeneThe 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.
NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.
NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2, MAML3 or MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters.
Annotated Interactions
coactivator
complex:p-S133-CREB1:EP300:GZMB Genecoactivator
complex:p-S133-CREB1:EP300:GZMB GeneJAG1-NOTCH2 signaling axis is affected in Alagille syndrome (AGS), a dominant congenital disorder characterized by hepatic bile duct abnormalities, as well as craniofacial, heart and kidney defects (Alagille et al. 1975, Habib et al. 1987). AGS is predominantly caused by mutations in JAG1 (Oda et al. 1997, Li et al. 1997) and less frequently by mutations in NOTCH2 (McDaniell et al. 2006).
JAG1 and NOTCH2 are expressed in kidney glomeruli and JAG1-NOTH2 signaling plays an important role in kidney development, as shown in mice mutant for JAG1 or NOTCH2 or both (McCright et al. 2001, McCright et al. 2002).
Besides NICD2, RBPJ and MAML, NOTCH2 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 NICD2, it is not shown here. More details are available in the pathway Signaling by NOTCH1.
Many NOTCH-regulated genes have paired RBPJ-binding sites in their promoters, in head-to-head arrangement, and require cooperative formation of dimeric NOTCH transcription complexes for transcriptional activation (Nam et al. 2007).