Reactome: A Curated Pathway Database

NOTCH1 Intracellular Domain Regulates Transcription

Stable Identifier
Homo sapiens
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NICD1 produced by activation of NOTCH1 in response to Delta and Jagged ligands (DLL/JAG) presented in trans, traffics to the nucleus where it acts as a transcription regulator. In the nucleus, NICD1 displaces the NCOR corepressor complex from RBPJ (CSL). When bound to the co-repressor complex that includes NCOR proteins (NCOR1 and NCOR2) and HDAC histone deacetylases, RBPJ (CSL) represses transcription of NOTCH target genes (Kao et al. 1998, Zhou et al. 2000, Perissi et al. 2004, Perissi et al. 2008). Once the co-repressor complex is displaced, NICD1 recruits MAML (mastermind-like) to RBPJ, while MAML recruits histone acetyltransferases EP300 (p300) and PCAF, resulting in formation of the NOTCH coactivator complex that activates transcription from NOTCH regulatory elements. The minimal functional NOTCH coactivator complex that activates transcription from NOTCH regulatory elements is a heterotrimer composed of NICD, MAML and RBPJ (Fryer et al. 2002, Wallberg et al. 2002, Nam et al. 2006).

NOTCH1 coactivator complex is known to activate transcription of HES1 (Jarriault et al. 1995), HES5 (Arnett et al. 2010), HEY genes (Fischer et al. 2004, Leimeister et al. 2000, Maier et al. 2000, Arnett et al. 2010) and MYC (Palomero et al. 2006) and likely regulates transcription of many other genes (Wang et al. 2011). NOTCH1 coactivator complex on any specific regulatory element may involve additional transcriptional regulatory proteins. HES1 binds TLE proteins, forming an evolutionarily conserved transcriptional corepressor involved in regulation of neurogenesis, segmentation and sex determination (Grbavec et al. 1996, Fisher et al. 1996, Paroush et al. 1994).

After NOTCH1 coactivator complex is assembled on a NOTCH-responsive promoter, MAML (mastermind-like) recruits CDK8 in complex with cyclin C, triggering phosphorylation of conserved serine residues in TAD and PEST domains of NICD1 by CDK8. Phosphorylated NICD1 is recognized by the E3 ubiquitin ligase FBXW7 which ubiquitinates NICD1, leading to degradation of NICD1 and downregulation of NOTCH1 signaling. FBXW7-mediated ubiquitination and degradation of NOTCH1 depend on C-terminally located PEST domain sequences in NOTCH1 (Fryer et al. 2004, Oberg et al. 2001, Wu et al. 2001). The PEST domain of NOTCH1 and the substrate binding WD40 domain of FBXW7 are frequent targets of mutations in T-cell acute lymphoblastic leukemia - T-ALL (Welcker and Clurman 2008).

NICD1, which normally has a short half-life, can be stabilized by binding to the hypoxia-inducable factor 1-alpha (HIF1A) which accumulates in the nucleus when oxygen levels are low. This results in HIF1A-induced inhibition of cellular differentiation that is NOTCH-dependent (Gustafsson et al. 2005).

Literature References
PubMed ID Title Journal Year
15107403 The Notch target genes Hey1 and Hey2 are required for embryonic vascular development Genes Dev 2004
16530044 Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes Cell 2006
8687460 Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif Biochem Biophys Res Commun 1996
21737748 Genome-wide analysis reveals conserved and divergent features of Notch1/RBPJ binding in human and murine T-lymphoblastic leukemia cells Proc. Natl. Acad. Sci. U.S.A. 2011
12391150 p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro Mol Cell Biol 2002
8649374 The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain Mol Cell Biol 1996
7566092 Signalling downstream of activated mammalian Notch Nature 1995
17114293 NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth Proc Natl Acad Sci U S A 2006
10964718 Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes Biochem Biophys Res Commun 2000
20972443 Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes Nat Struct Mol Biol 2010
11044625 Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos Mech Dev 2000
11461910 The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog J Biol Chem 2001
18374649 TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints Mol Cell 2008
9694793 A histone deacetylase corepressor complex regulates the Notch signal transduction pathway Genes Dev 1998
8001118 Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins Cell 1994
18094723 FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation Nat Rev Cancer 2008
12050117 Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex Genes Dev 2002
10713164 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function Mol Cell Biol 2000
14980219 A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors Cell 2004
16256737 Hypoxia requires notch signaling to maintain the undifferentiated cell state Dev Cell 2005
15546612 Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover Mol Cell 2004
11585921 SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation Mol Cell Biol 2001
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Orthologous Events