NOTCH4 Activation and Transmission of Signal to the Nucleus

Stable Identifier
R-HSA-9013700
Type
Pathway
Species
Homo sapiens
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NOTCH4 is co-expressed with DLL4 (Delta-4) and JAG1 (Jagged-1) in the vascular system (Shutter et al. 2000, Uyttendaele et al. 2000). NOTCH4 can be activated by DLL4 and JAG1 when HMVECd cells (human primary endothelial cell line derived from neonatal dermal microvasculature) or HUVEC cells (human umbilical venous endothelial cell line) expressing recombinant mouse Notch4 are co-cultured with HMVECd or HUVEC cells expressing recombinant human or mouse DLL4 (Shawber et al. 2003, Shawber et al. 2007) or mouse Jag1 (Shawber et al. 2007). Activation of NOTCH4 by DLL4 and JAG1 could not be reproduced when the mouse fibroblast cell line NIH 3T3 or human embryonic kidney cell line HEK293 was transduced with Notch4- or either Dll4- or Jag1-expressing vectors and used in co-culture experiments (Aste-Amezaga et al. 2010, James et al. 2014).

Signaling by NOTCH4, similar to other NOTCH family proteins, involves proteolytic cleavage of the membrane-bound NOTCH4 receptor and release of the NOTCH4 intracellular domain fragment (NICD4) into the cytosol (Saxena et al. 2001, Das et al. 2004). NICD4 traffics from the cytosol to the nucleus, where it acts as a transcription factor (Lin et al. 2002).

Literature References
PubMed ID Title Journal Year
11518718 Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis

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

J Biol Chem 2001
10837024 Dll4, a novel Notch ligand expressed in arterial endothelium

Shutter, JR, Scully, S, Fan, W, Richards, WG, Kitajewski, J, Deblandre, GA, Kintner, CR, Stark, KL

Genes Dev 2000
20161710 Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors

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

PLoS ONE 2010
12386158 Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling

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

J. Biol. Chem. 2002
17948123 Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression

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

J. Clin. Invest. 2007
15123653 Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function

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

J. Biol. Chem. 2004
20804727 Transforming acidic coiled-coil protein-3 (Tacc3) acts as a negative regulator of Notch signaling through binding to CDC10/Ankyrin repeats

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

Biochem. Biophys. Res. Commun. 2010
24667410 Notch4 reveals a novel mechanism regulating Notch signal transduction

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

Biochim. Biophys. Acta 2014
12814948 Notch signaling in primary endothelial cells

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

Ann. N. Y. Acad. Sci. 2003
10964583 Notch4 and Jagged-1 induce microvessel differentiation of rat brain endothelial cells

Uyttendaele, H, Closson, V, Wu, G, Roux, F, Weinmaster, G, Kitajewski, J

Microvasc. Res. 2000
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