NEXT1 is cleaved to produce NICD1

Stable Identifier
R-HSA-157353
Type
Reaction [transition]
Species
Homo sapiens
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NEXT1 fragment of NOTCH1 is further cleaved at S3 by the presenilin-1 (PSEN1) containing gamma-secretase complex, which releases the intracellular domain NICD1 into the cytosol (Schroeter et al. 1998, De Strooper et al. 1999, Huppert et al. 2000, Fortini et al. 2002). PIN1, a prolyl isomerase, was recently found to bind phosphorylated Ser/Thr-Pro motifs in the cytoplasmic domain of NOTCH1 and potentiate NEXT1 cleavage by gamma-secretase. This generates a positive loop in NOTCH1 signaling since PIN1 is a transcriptional target of NICD1 (Rustighi et al. 2009).

Literature References
PubMed ID Title Journal Year
19151708 The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer

Rustighi, A, Tiberi, L, Soldano, A, Napoli, M, Nuciforo, P, Rosato, A, Kaplan, F, Capobianco, A, Pece, S, Di Fiore, PP, Del Sal, G

Nat Cell Biol 2009
10879540 Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1

Huppert, SS, Le, A, Schroeter, EH, Mumm, JS, Saxena, MT, Milner, LA, Kopan, R

Nature 2000
12209127 Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling

Fortini, ME

Nat Rev Mol Cell Biol 2002
9620803 Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain

Schroeter, EH, Kisslinger, JA, Kopan, R

Nature 1998
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
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Title
aspartic-type endopeptidase activity of gamma-secretase complex [plasma membrane]
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