NOTCH3 Activation and Transmission of Signal to the Nucleus

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Homo sapiens
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NOTCH3 receptor can be activated by DLL/JAG ligands DLL1, JAG1, and JAG2 (Shimizu et al. 2000), as well as DLL4 (Claxton and Fruttiger 2004, Indraccolo et al. 2009). Ligand binding induces a conformational change in NOTCH3, which exposes the S2 site in the extracellular region of NOTCH3. The S2 site is cleaved by ADAM10 metalloprotease, generating the membrane anchored NOTCH3 fragment NEXT3. The NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma secretase complex, releasing the intracellular domain NICD3 into the cytosol (Groot et al. 2014). Besides DLL/JAG ligands, NOTCH3 signaling can also be activated by binding of NOTCH3 to YBX1 (YB 1) (Rauen et al. 2009). NICD3 traffics to the nucleus where it acts as a transcription factor. WWP2, an E3 ubiquitin ligase, negatively regulates NOTCH3 signaling by ubiquitinating NEXT3 and NICD3 in the cytosol and targeting them for lysosome-mediated degradation (Jung et al. 2014). NOTCH3 signaling is also negatively regulated by binding to TACC3 (Bargo et al. 2010) and by EGFR-mediated phosphorylation (Arasada et al. 2014).
Literature References
PubMed ID Title Journal Year
10958687 Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2

Kanda, Y, Kurokawa, M, Shimizu, K, Hirai, H, Kumano, K, Hamada, Y, Saito, T, Chiba, S, Hosoya, N

Mol Cell Biol 2000
24842903 Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins

Groot, AJ, Habets, R, Vooijs, M, Saftig, P, Hodin, CM, Theys, J, Reiss, K, Yahyanejad, S

Mol. Cell. Biol. 2014
19640841 YB-1 acts as a ligand for Notch-3 receptors and modulates receptor activation

Djudjaj, S, M├╝hlenberg, PJ, Raffetseder, U, Frye, BC, Eitner, F, Bernhagen, J, Lendahl, U, Mertens, PR, Dooley, S, Rauen, T

J. Biol. Chem. 2009
15533827 Periodic Delta-like 4 expression in developing retinal arteries

Claxton, S, Fruttiger, M

Gene Expr Patterns 2004
19208840 Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy

Pusceddu, I, Mecarozzi, M, Indraccolo, S, Amadori, A, Masiero, M, Minuzzo, S, Favaro, E, Screpanti, I, Reboldi, A, Di Mario, G, Ponzoni, M, Persano, L, Moserle, L, Doglioni, C

Cancer Res 2009
25125655 EGFR blockade enriches for lung cancer stem-like cells through Notch3-dependent signaling

Huppert, SS, Carbone, DP, Arasada, RR, Rahman, MA, Amann, JM

Cancer Res. 2014
25356737 Notch3 interactome analysis identified WWP2 as a negative regulator of Notch3 signaling in ovarian cancer

Wu, RC, Guan, B, Blackshaw, S, Wang, TL, Zhu, H, Stoeck, A, Shih, IeM, Jung, JG

PLoS Genet. 2014
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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