NOTCH1 HD domain mutants are cleaved to produce NEXT1 irrespective of ligand binding

Stable Identifier
R-HSA-2730752
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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When the gamma-secretase complex is inhibited, the transmembrane fragment of NOTCH1 HD domain mutants that corresponds in size to ADAM10/17 cleavage product NEXT1 accumulates in treated cells. This serves as indirect evidence of cleavage of NOTCH1 heterodimerization domain mutants by ADAM10/17 metalloprotease(s). Importantly, in the case of NOTCH1 HD domain mutants, NEXT1 fragment, as well as the gamma-secretase cleavage product NICD1, are detectable in the absence of DLL/JAG ligand binding. Therefore, NOTCH1 HD domain mutants, although capable of and responsive to ligand binding, are constitutively active because of S2 site cleavage by ADAM10/17 in the absence of ligand. The constitutive S2 site cleavage of NOTCH1 HD domain mutants could be due to their altered conformation or due to increased rate of spontaneous dissociation of NOTCH1 extracellular and transmembrane subunits (Malecki et al. 2006). Both of these scenarios could make the S2 site constitutively accessible to ADAM10/17, but the exact mechanism has not been established.

Literature References
PubMed ID Title Journal Year
9244301 Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis

Pan, D, Rubin, GM

Cell 1997
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
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
17401372 Structural basis for autoinhibition of Notch

Gordon, WR, Vardar-Ulu, D, Histen, G, Sanchez-Irizarry, C, Aster, JC, Blacklow, SC

Nat Struct Mol Biol 2007
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
16738328 Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes

Malecki, MJ, Sanchez-Irizarry, C, Mitchell, JL, Histen, G, Xu, ML, Aster, JC, Blacklow, SC

Mol. Cell. Biol. 2006
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
metallopeptidase activity of ADAM10/17:Zn2+ [plasma membrane]
Physical Entity
Activity
Disease
Name Identifier Synonyms
T-cell leukemia 715
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Authored
Reviewed
Created