Search results for NOTCH1

Showing 15 results out of 366

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Protein (3 results from a total of 68)

Identifier: R-HSA-2768982
Species: Homo sapiens
Compartment: plasma membrane
Primary external reference: UniProt: NOTCH1: P46531
Identifier: R-HSA-2220929
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: NOTCH1: P46531
In a small percent of T-ALL patients, the translocation t(7;9)(q34;q34.3) fuses intron 24 of NOTCH1 gene with the promoter of T cell receptor beta gene. This results in deregulated expression of a truncated NOTCH1 protein, which lacks ligand binding activity and is constitutivelu processed into NICD1 (Ellisen et al. 1991).
Identifier: R-HSA-2681764
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: NOTCH1: P46531

Complex (3 results from a total of 111)

Identifier: R-HSA-2902189
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2902190
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2193050
Species: Homo sapiens
Compartment: plasma membrane

Set (3 results from a total of 16)

Identifier: R-HSA-2220961
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2220939
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-2894870
Species: Homo sapiens
Compartment: plasma membrane

Pathway (3 results from a total of 30)

Identifier: R-HSA-2660825
Species: Homo sapiens
Human NOTCH1 was cloned as a chromosome 9 gene, translocated to the T-cell beta receptor (TCBR) promoter on chromosome 7 in T-cell acute lymphoblastic leukemia (T-ALL) (Ellisen et al. 1991). The translocated gene was found to be homologous to Drosophila Notch, and was initially named TAN-1 (translocation-associated Notch homolog). Although the translocation t(7;9)(q34;q34.3) is present in a small percentage of T-ALL patients, the mutant protein is highly oncogenic and its overexpression causes T-ALL-like illness in mice (Pear et al. 1996).
Identifier: R-HSA-2122948
Species: Homo sapiens
Compartment: plasma membrane, cytosol, nucleoplasm
Mature NOTCH1 heterodimer on the cell surface is activated by one of its ligands: DLL1 (Cordle et al. 2008, Jarriault et al. 1998), DLL4 (Benedito et al. 2009), JAG1 (Li et al. 1998, Benedito et al. 2009) or JAG2 (Luo et al. 1997, Shimizu et al. 2000), expressed in trans on a neighboring cell. Thus, a ligand-expressing cell is a signal-sending cell, while the NOTCH1 expressing cell is a signal-receiving cell. If NOTCH1 has undergone Fringe modification in the Golgi, it is preferentially activated by Delta ligands (Yang et al. 2005), DLL1 and DLL4.


Upon binding to NOTCH1 on a neighboring cell, NOTCH ligands are ubiquitinated by Mindbomb (MIB1 and MIB2) and/or Neuralized (NEURL and NEURL1B) E3 ubiquitin ligases and endocytosed (Koo et al. 2007, Koo et al. 2005, Itoh et al. 2003, Lai et al. 2001, Koutelou et al. 2008, Song et al. 2006). Endocytosis of ubiquitinated ligands is thought to mechanically stretch the bound NOTCH1 receptor, exposing a cleavage site S2 that is recognized by ADAM10 and/or ADAM17 metalloprotease (van Tetering et al. 2009, Brou et al. 2000, Hartmann et al. 2002, Pan et al. 1997). S2 cleavage of NOTCH1 produces the NEXT1 fragment which is further cleaved at an S3 cleavage site by the gamma-secretase complex, resulting in release of the NOTCH1 intracellular domain (NICD1) into the cytosol (de Strooper et al. 1999, Schroeter et al. 1998, Huppert et al. 2000). NICD1 produced by activation of NOTCH1 in response to in trans presented Delta and Jagged ligands (DLL/JAG) traffics to the nucleus where it acts as a transcription regulator.


NOTCH1 signaling can also be activated by ligands other than DLL1, DLL4, JAG1 and JAG2. CNTN1 (Contactin-1), transiently expressed during central and peripheral nervous system development, activates NOTCH1 and NOTCH2 in trans, promoting oligodendrocyte maturation and myelination (Hu et al. 2003). DNER (Delta and Notch-like epidermal growth factor-related receptor) is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. Activation of NOTCH1 by DNER in trans may play an important role in development of the central nervous system by influencing differentiation of astrocytes (Eiraku et al. 2005). Activation of NOTCH1 by both CNTN1 and DNER is Deltex (DTX)-dependent and results in gamma-secretase mediated release of NICD1. Three members of the Deltex protein family: DTX1, DTX2 and DTX4 possess a domain involved in binding cdc10/ankyrin repeats of NOTCH. DTX proteins are considered as positive regulators of NOTCH signaling, although the exact mechanism has not been elucidated (Matsuno et al. 1998, Kishi et al. 2001).In addition, DTX can mediate downregulation of NOTCH signaling by recruiting non-visual beta-arrestins to NOTCH (Mukherjee et al. 2005), thereby trigerring NOTCH ubiquitination. DTX proteins are negatively regulated by ITCH (AIP4) ubiquitin ligase (Chastagner et al. 2006).

NOTCH1 signaling in the signal-receiving cell can be turned off in cis by expression of NOTCH ligands DLL/JAG (Cordle et al. 2008, Sprinzak et al. 2010), as well as DLK1 (Baladron et al. 2005, Bray et al. 2008). Formation of NOTCH1:ligand complexes in cis prevents interaction of NOTCH1 with ligands expressed in trans, resulting in the inhibition of NOTCH signaling. In the signal-sending cell, NOTCH signaling can be negatively regulated by the protein NUMB, which is asymmetrically distributed during cell division (Rhyu et al. 1994). NUMB recruits ITCH ubiquitin ligase to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009, Chastagner et al. 2008).
Identifier: R-HSA-2122947
Species: Homo sapiens
Compartment: nucleoplasm
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).

Reaction (3 results from a total of 135)

Identifier: R-HSA-1980039
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
The NOTCH1 receptor is activated by binding Delta-like 1 ligand (DLL1), presented on the plasma membrane of a neighboring cell (Jarriault et al. 1998). EGF repeat 12 (EGF12) in the extracellular domain of NOTCH1 appears to be particularly important for interaction of NOTCH1 with DLL1 (Cordle et al. 2008). The affinity of NOTCH1 for DLL1 is increased when NOTCH1 is glycosylated by fringe enzymes (Yang et al 2005).
Identifier: R-HSA-1980041
Species: Homo sapiens
Compartment: extracellular region
NOTCH1 is activated by DLL4 ligand expressed on a neighboring cell. The interaction of NOTCH1 and DLL4 is enhanced when NOTCH1 is glycosylated by fringe-enzymes. Based on mouse studies, activation of NOTCH1 by DLL4 may be important in angiogenesis (Benedito et al. 2009). DLL4 may also be involved in T-cell development. Mouse Dll4 is expressed on thymic epithelial cells and its interaction with Notch1 expressed on hematopoietic progenitors is necessary for T-cell lineage commitment (Koch et al. 2008, Hozumi et al. 2008).
Identifier: R-HSA-1980130
Species: Homo sapiens
Compartment: plasma membrane
DLK1 is a Delta-like transmembrane protein with six extracellular EGF repeats and a short intracellular tail. DLK1 is encoded by a paternally imprinted gene and, based on mouse studies, is implicated in many developmental processes, such as adipogenesis, hematopoiesis, differentiation of adrenal gland and other neuroendocrine cells, as well as development of the central nervous system. Mice lacking Dlk1 exhibit growth retardation and obesity. Based on studies done in mice and flies, NOTCH1 and DLK1 interact to form a complex, most likely in cis, which results in the inhibition of NOTCH1 signaling by preventing NOTCH1 interaction with DLL and JAG ligands (Baladron et al. 2005, Bray et al. 2008). Besides its inhibitory role, DLK1 may function as a coactivator for NOTCH receptors. DLK1 possesses a Delta and OSM-11 motif (DOS), which has been found in C. elegans proteins that facilitate Notch activation in trans by DSL family ligands. The mammalian DLK1 can substitute for OSM-11 protein in C. elegans development (Komatsu et al. 2008).
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