Reactome | NOTCH2 Activation and Transmission of Signal to the Nucleus

NOTCH2 Activation and Transmission of Signal to the Nucleus

Stable Identifier

R-HSA-2979096

DOI

10.3180/R-HSA-2979096.5

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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NOTCH2 Activation and Transmission of Signal to the Nucleus

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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
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
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
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
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
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
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
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
11518718	Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis Saxena, MT, Schroeter, EH, Mumm, JS, Kopan, R	J Biol Chem	2001
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