NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding

Stable Identifier
R-HSA-2220976
Type
Reaction [transition]
Species
Homo sapiens
Compartment
extracellular region, plasma membrane
ReviewStatus
5/5
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NOTCH1 HD+PEST domain mutants are cleaved by ADAM10/17 irrespective of ligand binding
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NOTCH1 HD domain mutants are cleaved at S2 and S3 sites to produce NEXT1 and NICD1 fragments, respectively, in the absence of DLL/JAG ligand binding, although they are responsive to DLL/JAG ligands. NOTCH1 mutants containing in cis mutations in the HD and PEST domains are expected to be constitutively cleaved at the S2 site by ADAM10/17, like NOTCH1 HD domain mutants (Malecki et al. 2006), resulting in release of NEXT1 PEST domain mutant fragments.
Literature References
PubMed ID Title Journal Year
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
Input
Output
Entity On Other Cell
Participates
as an event of
Catalyst Activity

metallopeptidase activity of ADAM10/17:Zn2+ [plasma membrane]

Physical Entity
ADAM10/17:Zn2+ [plasma membrane] (Homo sapiens)
Activity
metallopeptidase activity (GO:0008237)
Functional status

Gain of function of NOTCH1 HD+PEST Domain Mutants/Ub-DLL/JAG:NOTCH1 HD+PEST Domain Mutants [plasma membrane]

Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
T-cell acute lymphoblastic leukemia DOID:5603
Cross References
Mondo
Authored
Orlic-Milacic, M  (2013-01-04)
Reviewed
Haw, R  (2013-02-10)
Created
Orlic-Milacic, M  (2012-05-03)
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