Murine ADAM10 cleaves Notch at the S2 site producing transmembrane spanning NEXT and ligand-bound NECD

Stable Identifier
R-NUL-209162
Type
Reaction [transition]
Species
Mus musculus
Compartment
General
SVG |   | PPTX  | SBGN
Murine ADAM10 cleaves Notch at the S2 site producing transmembrane spanning NEXT and ligand-bound NECD

Cleavage of mouse Notch1 at the S2 site precedes the gamma-secretase-mediated cleavage at the S3 site. It was initially shown that a membrane bound mouse Notch1 fragment exogenously expressed in HEK 293 cells is cleaved at S2 by human ADAM17 isolated from HeLa cells (Brou et al. 2000). However, experiments in which Notch1 cleavage at S2 was examined in mouse fibroblasts deficient for one of the Adam enzymes (Adam9, Adam10, Adam12, Adam15 or Adam17), stimulated by co-culture with cells expressing mouse Jag1, showed that Adam10, a homologue of Drosophila Kuzbanian, was required for the S2 cleavage (van Tetering et al. 2009). Adam10 knockout mice die at embryonal day 9.5 with multiple defects in the developing central nervous system, somites and cardiovascular system. The neural tube of Adam10 deficient embryos exhibits decreased expression of the Notch gene target Hes5 (Hartmann et al. 2002).

Literature References
PubMed ID Title Journal Year
10882063 A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE

Brou, C, Logeat, F, Gupta, N, Bessia, C, LeBail, O, Doedens, JR, Cumano, A, Roux, P, Black, RA, Israel, A

Mol Cell 2000
12354787 The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts

Hartmann, D, De Strooper, B, Serneels, L, Craessaerts, K, Herreman, A, Annaert, W, Umans, L, L├╝bke, T, Lena Illert, A, von Figura, K, Saftig, P

Hum Mol Genet 2002
19726682 Metalloprotease ADAM10 is required for Notch1 site 2 cleavage

van Tetering, G, van Diest, P, Verlaan, I, van der Wall, E, Kopan, R, Vooijs, M

J Biol Chem 2009
Participants
Catalyst Activity

metalloendopeptidase activity of Adam10 [plasma membrane]

Orthologous Events
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