NOTCH3 Intracellular Domain Regulates Transcription

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Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
18593473 Reelin induces a radial glial phenotype in human neural progenitor cells by activation of Notch-1

Sugaya, K, Keilani, S

BMC Dev. Biol. 2008
16368887 Cross talk among Notch3, pre-TCR, and Tal1 in T-cell development and leukemogenesis

Vacca, A, Pascucci, M, Cialfi, S, Gulino, A, Frati, L, Palermo, R, Screpanti, I, Oliviero, C, Talora, C

Blood 2006
12386158 Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling

Oyama, T, Nagase, T, Lin, SE, Kitagawa, M, Harigaya, K

J. Biol. Chem. 2002
17332745 Notch3 and the Notch3-upregulated RNA-binding protein HuD regulate Ikaros alternative splicing

Mecarozzi, M, Campese, AF, Gulino, A, Frati, L, Screpanti, I, Grazioli, P, Talora, C, Bellavia, D

EMBO J. 2007
11866432 Functional diversity among Notch1, Notch2, and Notch3 receptors

Shimizu, K, Hirai, H, Kumano, K, Hamada, Y, Saito, T, Chiba, S

Biochem Biophys Res Commun 2002
18974129 Identification of Pbx1, a potential oncogene, as a Notch3 target gene in ovarian cancer

Park, JT, Wang, TL, Shih, IeM

Cancer Res. 2008
18032925 Notch and Ikaros: not only converging players in T cell leukemia

Mecarozzi, M, Gulino, A, Campese, AF, Screpanti, I, Grazioli, P, Bellavia, D

Cell Cycle 2007
11971902 Coordinate Notch3-hairy-related transcription factor pathway regulation in response to arterial injury. Mediator role of platelet-derived growth factor and ERK

Prince, CZ, Wang, W, Pollman, MJ, Mou, Y, Campos, AH

J. Biol. Chem. 2002
16498412 Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia

Vacca, A, Gulino, A, Frati, L, Palermo, R, Felli, MP, Screpanti, I, Di Giovine, M, Di Mario, G, Calce, A

EMBO J. 2006
22396495 Defining NOTCH3 target genes in ovarian cancer

Chen, X, Gao, M, Xuan, J, Chen, L, Wang, TL, Stoeck, A, Shih, IeM, Thiaville, MM

Cancer Res. 2012
16365048 Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability

Kopan, R, Cheng, HT, Chang, LW, Stormo, GD, Ong, CT, Kageyama, R, Ohtsuka, T

J. Biol. Chem. 2006
27749937 PlexinD1 Is a Novel Transcriptional Target and Effector of Notch Signaling in Cancer Cells

Rehman, M, Gurrapu, S, Capparuccia, L, Tamagnone, L, Cagnoni, G

PLoS ONE 2016
27841855 Notch3 inhibits epithelial-mesenchymal transition by activating Kibra-mediated Hippo/YAP signaling in breast cancer epithelial cells

Li, Y, Zhang, X, Chen, M, Liu, X, Ye, X, Luo, J, Zhang, GJ, Xiao, W

Oncogenesis 2016
14566327 Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma

Pascucci, M, Campese, AF, von Boehmer, H, Checquolo, S, Gulino, A, Frati, L, Screpanti, I, Groppioni, M, Talora, C, Bellavia, D

EMBO Rep. 2003
15879553 Brain lipid-binding protein is a direct target of Notch signaling in radial glial cells

Gridley, T, Heintz, N, Fishell, G, Mason, HA, Anthony, TE

Genes Dev. 2005
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