NOTCH4 Intracellular Domain Regulates Transcription

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Homo sapiens
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In the nucleus, NOTCH4 intracellular domain fragment (NICD4) binds transcription factors RBPJ (CSL) and mastermind family members (MAML1, MAML2 or MAML3) to form the NOTCH4 co-activator complex (Lin et al. 2002). The NOTCH4 coactivator complex stimulates transcription of well-established NOTCH targets HES1, HES5, HEY1 and HEY2 in a cellular context-dependent manner (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Bargo et al. 2010). NOTCH4 also stimulates transcription of the FLT4 (VEGFR3) gene, encoding vascular endothelial growth factor receptor-3 (Shawber et al. 2007) and ACTA2 gene, encoding smooth muscle alpha actin (Tang et al. 2008).

NICD4 inhibits TGF-beta-induced SMAD-mediated transcription via binding of NICD4 to TGF-beta activated SMAD3 (Sun et al. 2005, Grabias and Konstantopoulos 2013).

Literature References
PubMed ID Title Journal Year
23576639 Notch4-dependent antagonism of canonical TGF-β1 signaling defines unique temporal fluctuations of SMAD3 activity in sheared proximal tubular epithelial cells

Konstantopoulos, K, Grabias, BM

Am. J. Physiol. Renal Physiol. 2013
14672936 Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development

Tsunematsu, R, Oike, Y, Bessho, Y, Hatakeyama, S, Nakayama, KI, Suda, T, Nakayama, K, Kageyama, R, Ishida, N, Nishiyama, M

J. Biol. Chem. 2004
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
18239137 Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site

Liaw, L, Tang, Y, Urs, S

Circ. Res. 2008
17948123 Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression

Feirt, N, Vorontchikhina, M, Chawengsaksophak, K, Borisenko, V, Stowell, SA, Shiraishi, K, Shawber, CJ, Skobe, M, Kitajewski, J, Podgrabinska, S, Francisco, E, Kitamura, Y, Rossant, J, Accili, D, Funahashi, Y

J. Clin. Invest. 2007
15531924 Mammary development and tumorigenesis in mice expressing a truncated human Notch4/Int3 intracellular domain (h-Int3sh)

Bargo, S, Callahan, R, Raafat, A, Anver, MR

Oncogene 2004
16007227 Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling

Bianco, C, Strizzi, L, Raafat, D, Bargo, S, Sun, Y, Hirota, M, Callahan, R, Kato, K, Kenney, N, Khan, NI, Salomon, D, Jones, B, Lowther, W

Oncogene 2005
20804727 Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats

Bargo, S, Shu, Y, Callahan, R, Plant, J, Raafat, A, McCurdy, D, Vonderhaar, BK, Amirjazil, I, Traicoff, J

Biochem. Biophys. Res. Commun. 2010
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