NOTCH2 Activation and Transmission of Signal to the Nucleus

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R-HSA-2979096
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Pathway
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Homo sapiens
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Similar to NOTCH1, NOTCH2 is activated by Delta-like and Jagged ligands (DLL/JAG) expressed in trans on a neighboring cell (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). The activation triggers cleavage of NOTCH2, first by ADAM10 at the S2 cleavage site (Gibb et al. 2010, Shimizu et al. 2000), then by gamma-secretase at the S3 cleavage site (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 subsequently traffics to the nucleus where it acts as a transcription regulator.

While DLL and JAG ligands are well established, canonical NOTCH2 ligands, there is limited evidence that NOTCH2, similar to NOTCH1, can be activated by CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003). MDK (midkine), which plays an important role in epithelial to mesenchymal transition, can also activate NOTCH2 signaling and is able to bind to the extracellular domain of NOTCH2, but the exact mechanism of MDK-induced NOTCH2 activation has not been elucidated (Huang et al. 2008, Gungor et al. 2011).

Literature References
PubMed ID Title Journal Year
10934472 Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2

Hicks, C, Johnston, SH, diSibio, G, Collazo, A, Vogt, TF, Weinmaster, G

Nat Cell Biol 2000
10958687 Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2

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

Mol Cell Biol 2000
11518718 Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis

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

J Biol Chem 2001
18469519 Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes

Huang, Y, Hoque, MO, Wu, F, Trink, B, Sidransky, D, Ratovitski, EA

Cell Cycle 2008
21632553 Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer

Güngör, C, Zander, H, Effenberger, KE, Vashist, YK, Kalinina, T, Izbicki, JR, Yekebas, E, Bockhorn, M

Cancer Res. 2011
14567914 F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation

Hu, QD, Ang, BT, Karsak, M, Hu, WP, Cui, XY, Duka, T, Takeda, Y, Chia, W, Sankar, N, Ng, YK, Ling, EA, Maciag, T, Small, D, Trifonova, R, Kopan, R, Okano, H, Nakafuku, M, Chiba, S, Hirai, H, Aster, JC, Schachner, M, Pallen, CJ, Watanabe, K, Xiao, ZC

Cell 2003
10551863 Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods

Shimizu, K, Chiba, S, Kumano, K, Hosoya, N, Takahashi, T, Kanda, Y, Hamada, Y, Yazaki, Y, Hirai, H

J Biol Chem 1999
10206645 A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain

De Strooper, B, Annaert, W, Cupers, P, Saftig, P, Craessaerts, K, Mumm, JS, Schroeter, EH, Schrijvers, V, Wolfe, MS, Ray, WJ, Goate, A, Kopan, R

Nature 1999
20156974 ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

Gibb, DR, El Shikh, M, Kang, DJ, Rowe, WJ, El Sayed, R, Cichy, J, Yagita, H, Tew, JG, Dempsey, PJ, Crawford, HC, Conrad, DH

J Exp Med 2010
15569487 Function of Delta4 gene and its effects on 32D cell differentiation

Ji, CY, Cui, CS, Ma, DX, Zhao, JQ, Guo, NJ, Zhang, MH

Chin Med J (Engl) 2004
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