NOTCH2 intracellular domain regulates transcription

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Homo sapiens
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In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). NICD2:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (RBEs) (Wu et al. 2000). Besides NICD2, RBPJ and MAML, NOTCH2 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex.

NOTCH2 coactivator complex directly stimulates transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets.

The promoter of FCER2 (CD23A) contains several RBEs that are occupied by NOTCH2 but not NOTCH1 coactivator complexes, and NOTCH2 activation stimulates 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. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBEs, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002).

NOTCH2 coactivator complex occupies the proximal RBE of the GZMB (granzyme B) promoter and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008). NOTCH2 coactivator complex together with CREBP1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008).

There are indications that NOTCH2 genetically interacts with hepatocyte nuclear factor 1-beta (HNF1B) in kidney development (Massa et al. 2013, Heliot et al. 2013) and with hepatocyte nuclear factor 6 (HNF6) in bile duct formation (Vanderpool et al. 2012), but the exact nature of these genetic interactions has not been defined.

Literature References
PubMed ID Title Journal Year
23362348 HNF1B controls proximal-intermediate nephron segment identity in vertebrates by regulating Notch signalling components and Irx1/2

Desgrange, A, Buisson, I, Vainio, S, Prunskaite-Hyyryläinen, R, Shan, J, Heliot, C, Cereghini, S, Umbhauer, M

Development 2013
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
11986231 Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia

Shehata, M, Berger, R, Schwarzmeier, JD, Duechler, M, Hilgarth, M, Hubmann, R, Dettke, M

Blood 2002
21898486 Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo

Vanderpool, C, Huppert, SS, Gannon, M, Huppert, KA, Means, AL, Sparks, EE

Hepatology 2012
18724371 Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity

Saito, T, Sakata-Yanagimoto, M, Kurihara, T, Sone, S, Taniuchi, I, Kojima, H, Minato, Y, Kitamura, A, Ishifune, C, Yasutomo, K, Chiba, S, Yagita, H, Maekawa, Y

Nat. Immunol. 2008
23362349 Hepatocyte nuclear factor 1β controls nephron tubular development

Garbay, S, Bouvier, R, Heidet, L, Fischer, E, Massa, F, Gubler, MC, Pontoglio, M, Sugitani, Y, Noda, T

Development 2013
11101851 MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors

Blacklow, SC, Artavanis-Tsakonas, S, Aster, JC, Wu, L, Griffin, JD, Lake, R

Nat Genet 2000
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