Signaling by NOTCH4

Stable Identifier
Homo sapiens
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The NOTCH4 gene locus was discovered as a frequent site of insertion for the proviral genome of the mouse mammary tumor virus (MMTV) (Gallahan and Callahan 1987). MMTV-insertion results in aberrant expression of the mouse mammary tumor gene int-3, which was subsequently discovered to represent the intracellular domain of Notch4 (Robbins et al. 1992, Uyttendaele et al. 1996).

NOTCH4 is prevalently expressed in endothelial cells (Uyttendaele et al. 1996). DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells (Shawber et al. 2003, Shawber et al. 2007), but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested (Aste-Amezaga et al. 2010, James et al. 2014). The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4) (Saxena et al. 2001, Das et al. 2004). NICD4 traffics to the nucleus where it acts as a transcription factor and stimulates expression of NOTCH target genes HES1, HES5, HEY1 and HEY2, as well as VEGFR3 and ACTA2 (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Shawber et al. 2007, Tang et al. 2008, Bargo et al. 2010). NOTCH4 signaling can be downregulated by AKT1 phosphorylation-induced cytoplasmic retention (Ramakrishnan et al. 2015) as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination (Wu et al. 2001, Tsunematsu et al. 2004).

NOTCH4 was reported to inhibit NOTCH1 signaling in-cis, by binding to NOTCH1 and interfering with the S1 cleavage of NOTCH1, thus preventing production of functional NOTCH1 heterodimers at the cell surface (James et al. 2014).

NOTCH4 is involved in development of the vascular system. Overexpression of constitutively active Notch4 in mouse embryonic vasculature results in abnormal vessel structure and patterning (Uyttendaele et al. 2001). NOTCH4 may act to inhibit apoptosis of endothelial cells (MacKenzie et al. 2004).

Expression of int-3 interferes with normal mammary gland development in mice and promotes tumorigenesis. The phenotype of mice expressing int-3 in mammary glands is dependent on the presence of Rbpj (Raafat et al. 2009). JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with elevated expression of NOTCH target genes HES1, HEY1 and HEY2, and is associated with increased population of breast cancer stem cells and distant metastases (Simoes et al. 2015). Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling (Raafat et al. 2006) and on int-3-induced activaton of NFKB signaling (Raafat et al. 2017). In head and neck squamous cell carcinoma (HNSCC), high NOTCH4 expression correlates with elevated HEY1 levels, increased cell proliferation and survival, epithelial-to-mesenchymal transition (EMT) phenotype and cisplatin resistance (Fukusumi et al. 2018). In melanoma, however, exogenous NOTCH4 expression correlates with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016). NOTCH4 is frequently overexpressed in gastric cancer. Increased NOTCH4 levels correlate with activation of WNT signaling and gastric cancer progression (Qian et al. 2015).

NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation (Lai et al. 2013).

During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner (Li et al. 2015). NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4 (Kusano and Raab-Traub 2001).
Literature References
PubMed ID Title Journal Year
29146722 The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma

Gutkind, JS, Sakai, A, Liu, C, Guo, TW, Califano, JA, Fukusumi, T, Haft, S, Ando, M, Ren, S, Amornphimoltham, P

Clin. Cancer Res. 2018
11344305 Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium

Rossant, J, Kitajewski, J, Uyttendaele, H, Ho, J

Proc. Natl. Acad. Sci. U.S.A. 2001
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
11119607 An Epstein-Barr virus protein interacts with Notch

Kusano, S, Raab-Traub, N

J. Virol. 2001
14701863 Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways

MacKenzie, F, Wong, F, Karsan, A, Duriez, P, Noseda, M

J. Biol. Chem. 2004
29057904 The ANK repeats of Notch-4/Int3 activate NF-κB canonical pathway in the absence of Rbpj and causes mammary tumorigenesis

Bargo, S, Callahan, R, Raafat, A, McCurdy, D

Sci Rep 2017
8681805 Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene

Wu, G, Marazzi, G, Uyttendaele, H, Kitajewski, J, Yan, Q, Sassoon, D

Development 1996
11518718 Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis

Saxena, MT, Kopan, R, Schroeter, EH, Mumm, JS

J Biol Chem 2001
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
15123653 Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function

Das, I, Craig, C, Kim, TW, Kutok, JL, Aster, JC, Kitajewski, J, Weng, AP, Jung, KM, Funahashi, Y, Byers, R

J. Biol. Chem. 2004
18836481 Rbpj conditional knockout reveals distinct functions of Notch4/Int3 in mammary gland development and tumorigenesis

Buono, K, Raafat, A, Bargo, S, Callahan, R, Klauzinska, M, Goldhar, AS, Lawson, S, Vonderhaar, BK, Strizzi, L, Salomon, D

Oncogene 2009
23237809 Active form Notch4 promotes the proliferation and differentiation of 3T3-L1 preadipocytes

Tsai, CB, Lai, PY, Tseng, MJ

Biochem. Biophys. Res. Commun. 2013
20161710 Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors

Huber, HE, Bett, AJ, L'Heureux, S, Wang, H, Toner, TJ, Huang, L, Blacklow, SC, Vo, KT, Aste-Amézaga, M, Gordon, WR, Tiyanont, K, Wang, F, Baleydier, F, Aster, JC, Zhao, JZ, Chastain, M, Thoryk, E, Arnold, BA, Zhang, N, Ross, KN, Roti, G, Stegmaier, K, Andrawes, MB, Haytko, P, Lineberger, JE, Vitelli, S, Franlin, LL, Gu, M, Wang, H, Audoly, LP

PLoS ONE 2010
25511451 Notch4 promotes gastric cancer growth through activation of Wnt1/β-catenin signaling

Ye, B, Liu, F, Qian, C, Liang, Y, Zhang, X, Yao, J

Mol. Cell. Biochem. 2015
25041739 Dengue virus up-regulates expression of notch ligands Dll1 and Dll4 through interferon-β signalling pathway

Pu, J, Li, Y, Wu, S, Huang, X, Zhang, P

Immunology 2015
16878155 Kit and PDGFR-alpha activities are necessary for Notch4/Int3-induced tumorigenesis

Raafat, A, Bargo, S, Callahan, R, Zoltan-Jones, A, Kimura, K, Strizzi, L, Salomon, D

Oncogene 2007
24667410 Notch4 reveals a novel mechanism regulating Notch signal transduction

Chapman, G, Szot, JO, James, AC, Iyer, K, Dunwoodie, SL, Major, JA, Pursglove, SE

Biochim. Biophys. Acta 2014
3023708 Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors

Callahan, R, Gallahan, D

J. Virol. 1987
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
1312643 Mouse mammary tumor gene int-3: a member of the notch gene family transforms mammary epithelial cells

Blondel, BJ, Callahan, R, Gallahan, D, Robbins, J

J. Virol. 1992
12814948 Notch signaling in primary endothelial cells

Das, I, Shawber, CJ, Kitajewski, J, Francisco, E

Ann. N. Y. Acad. Sci. 2003
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
26801977 Notch4 Signaling Induces a Mesenchymal-Epithelial-like Transition in Melanoma Cells to Suppress Malignant Behaviors

Bonyadi Rad, E, Bergler, H, Hafner, C, Hammerlindl, H, Ravindran Menon, D, Schaider, H, Herlyn, M, Popper, U, Breiteneder, H, Wels, C, Kitzwoegerer, M

Cancer Res. 2016
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
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
26387946 Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

Sims, AH, Brennan, K, Howell, SJ, Yu, L, Ucar, A, Alférez, DG, Gandhi, A, Farnie, G, Gee, J, Silva, A, Howell, A, Rydén, L, Clarke, RB, Catalano, S, Santiago-Gómez, A, Landberg, G, Marangoni, E, Eyre, R, Simões, BM, Spence, K, Chemi, F, O'Brien, CS, Andó, S, Acar, A, Sarmiento-Castro, A

Cell Rep 2015
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
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