NOTCH2-ligand complex is cleaved to produce NEXT2

Stable Identifier
R-HSA-157629
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane
ReviewStatus
5/5
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NOTCH2-ligand complex is cleaved to produce NEXT2
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Ligand binding induces a conformational change in NOTCH2, through mechanical pulling of NOTCH triggered by endocytosis of the receptor-attached ligand (Meloty-Kapella et al. 2012). This conformational change exposes the S2 site in the extracellular region of NOTCH2 and results in cleavage of NOTCH2 by ADAM10 metalloprotease (Gibb et al. 2010, Groot et al. 2014), generating the membrane-anchored NOTCH2 fragment NEXT2 (Shimizu et al. 2000). The extracellular NOTCH2 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
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

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

Mol Cell Biol 2000
22658936 Notch ligand endocytosis generates mechanical pulling force dependent on dynamin, epsins, and actin

Meloty-Kapella, L, Shergill, B, Kuon, J, Botvinick, E, Weinmaster, G

Dev. Cell 2012
24842903 Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins

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

Mol. Cell. Biol. 2014
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
Participants
Input
Output
Entity On Other Cell
Participates
as an event of
Catalyst Activity

metallopeptidase activity of ADAM10:Zn2+ [plasma membrane]

Physical Entity
ADAM10:Zn2+ [plasma membrane] (Homo sapiens)
Activity
metallopeptidase activity (GO:0008237)
Inferred From
Adam10 cleaves Notch2 (Mus musculus)
Authored
Orlic-Milacic, M  (2013-01-11)
Reviewed
Boyle, S  (2013-04-25)
Ilagan, MXG  (2013-04-25)
Created
Jassal, B  (2005-01-04)
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