An official website of the United States government

NOTCH3 Intracellular Domain Regulates Transcription

Source
Taxonomic Scope
organism_specific
Category
pathway
Dates
  • Create:
    2019-01-17
  • Modify:
    2025-01-01
Description
In the nucleus, NICD3 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind) proteins MAML1, MAML2 or MAML3 (possibly also MAMLD1). NICD3:RBPJ:MAML complex, also known as the NOTCH3 coactivator complex, activates transcription from RBPJ-binding promoter elements (Lin et al. 2002). While NOTCH1 prefers paired RBPJ binding sites, NOTCH3 preferentially binds to single RBPJ binding sites (Ong et al. 2006). NOTCH3 coactivator complex induces transcription of the well established NOTCH target genes HES1 (Lin et al. 2002, Boelens et al. 2014), HEYL (Maier and Gessler 2000, Geimer Le Lay et al. 2014), HES5 (Lin te al. 2002, Shimizu et al. 2002), and HEY2 (Wang et al. 2002). NOTCH3 positively regulates transcription of the pre-T-cell receptor alpha chain (PTCRA, commonly known as pT-alpha or pre-TCRalpha) (Talora et al. 2003, Bellavia et al. 2007). IK1, splicing isoform of the transcription factor Ikaros (IKZF1), competes with RBPJ for binding to the PTCRA promoter and inhibits PTCRA transcription. NOTCH3, through pre-TCR signaling, stimulates expression of the RNA binding protein HuD, which promotes splicing of IKZF1 into dominant negative isoforms. These dominant negative isoforms of IKZF1 heterodimerize with IK1, preventing its binding to target DNA sequences and thus contributing to sustained transcription of PTCRA (Bellavia et al. 2007, reviewed by Bellavia, Mecarrozzi, Campese, Grazioli, Gulino and Screpanti 2007). NOTCH3-triggered pre-TCR-signaling downregulates the activity of the transcription factor TCF3 (E2A), through ERK-dependent induction of ID1. Inhibition of TCF3-mediated transcription downstream of NOTCH3 contributes to development of T-cell lymphomas in transgenic mice expressing NICD3 (Talora et al. 2003). Activation of ERKs downstream of NOTCH3-stimulated pre-TCR signaling leads to phosphorylation of the transcription factor TAL1, formation of the TAL1:SP1 complex, and activation of cyclin D1 (CCND1) transcription, which stimulates cell division (Talora et al. 2006). NOTCH3 signaling can activate NF-kappaB (NFKB)-mediate transcription either indirectly, through activation of pre-TCR signaling, or directly, through association of NOTCH3 with IKKA. NFKB is constitutively active in T lymphoma cells derived from NOTCH3 transgenic mice (Vacca et al. 2006). Transcription of the PLXND1 gene, encoding the semaphorin receptor Plexin D1, is directly stimulated by NOTCH1 and NOTCH3 coactivator complexes. PLXND1 is involved in neuronal migration and cancer cell invasiveness (Rehman et al. 2016). Expression of FABP7 (BLBP) in radial glia is positively regulated by NOTCH1 and NOTCH3 during neuronal migration (Anthony et al. 2005, Keilani and Sugaya 2008). NOTCH3 gene is frequently amplified in ovarian cancer (Park et al. 2006). NOTCH3 coactivator complex directly stimulates DLGAP5 transcription. DLGAP5 is involved in G2/M transition and is overexpressed in ovarian cancer cells. (Chen et al. 2012). Another gene overexpressed in ovarian cancer whose transcription is directly stimulated by NOTCH3 is PBX1 (Park et al. 2008). The NOTCH3 coactivator complex directly stimulates WWC1 gene transcription. WWC1 gene encodes protein Kibra, involved in Hippo signaling. NOTCH3-mediated induction of WWC1 positively regulates Hippo signaling and inhibits epithelial-to-mesenchymal transition (EMT) in triple negative breast cancer cells (Zhang et al. 2016).

1 Identity

1.1 Source

1.2 External ID

2 Proteins

2.1 GlycoProteins

PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein
PubChem Protein
GlycoProtein

3 Genes

5 Literature

5.1 Consolidated References

6 Information Sources

  1. Reactome
    LICENSE
    Reactome is an open source and open access resource, available to anyone and covered by two Creative Commons licenses: the terms of the Creative Commons Public Domain (CC0) License apply to all Reactome annotation files, e.g. identifier mapping data, specialized data files, and interaction data derived from Reactome; the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License apply to all software and code, e.g. relating to the functionality of the reactome.org, derived websites and webservices, the Curator Tool, the Functional Interaction application, SQL and Graph Database data dumps, and Pathway Illustrations (Enhanced High-Level Diagrams), Icon Library, Art and Branding Materials.
    https://reactome.org/license
  2. PubChem
  3. GlyCosmos Glycoscience Portal
    LICENSE
    All copyrightable parts of the datasets in GlyCosmos are under the Creative Commons Attribution (CC BY 4.0) License.
    https://glycosmos.org/license
CONTENTS