Negative regulation of NOTCH4 signaling

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Homo sapiens
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NOTCH4 signaling can be negatively regulated at the level of nuclear translocation of the NOTCH4 intracellular domain fragment (NICD4). AKT-mediated phosphorylation of NICD4 promotes binding of NICD4 with 14-3-3-zeta (YWHAZ), leading to retention of NICD4 in the cytosol (Ramakrishnan et al. 2015).

The E3 ubiquitin ligase FBXW7, a component of the SCF ubiquitin ligase complex, binds to and ubiquitinates phosphorylated NICD4, targeting it for proteasome-mediated degradation (Wu et al. 2001). The level of NICD4 is significantly increased in Fbxw7 knockout mouse embryos, which die in utero and have impaired development of the vascular system (Tsunematsu et al. 2004).

Binding of NOTCH4 to ELOC (elongin C) is involved in proteasome-mediated degradation of NOTCH4, but the exact mechanism has not been elucidated (Cummins et al. 2011). MDM2, a TP53-induced ubiquitin ligase, was reported to ubiquitinate NICD4 and target it for degradation in response to TP53 activation (Sun et al. 2011).

NOTCH4 signaling is inhibited by binding of NICD4 to the transforming acidic coiled-coil protein-3, but he mechanism is not known (Bargo et al. 2010).

Literature References
PubMed ID Title Journal Year
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
25740432 AKT and 14-3-3 regulate Notch4 nuclear localization

Green, AR, Davaakhuu, G, Pannuti, A, Ramakrishnan, G, Zhu, H, Chung, WC, Miele, L, Atfi, A, Tzivion, G, Rana, A, Filipovic, A

Sci Rep 2015
22001063 Elongin C is a mediator of Notch4 activity in human renal tubule cells

Cummins, TD, Korte, EA, Khundmiri, SJ, Klein, JB, Barati, MT, Powell, DW, Mendenhall, MD, Lowry, MN, Salyer, SA

Biochim. Biophys. Acta 2011
11585921 SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation

Das, I, Wu, G, Deshaies, RJ, Kitajewski, J, Li, J, Pauley, A, Chui, I, Gurney, M, Lyapina, S

Mol Cell Biol 2001
21402876 Trp53 regulates Notch 4 signaling through Mdm2

Lee, JM, Klauzinska, M, Sun, Y, Callahan, R, Santopietro, S, Artavanis-Tsakonas, S, Salomon, D, Raafat, A, Lake, RJ

J. Cell. Sci. 2011
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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