Reactome | NEXT1 is cleaved to produce NICD1

NEXT1 is cleaved to produce NICD1

Stable Identifier

R-HSA-157353

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

ReviewStatus

5/5

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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
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
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
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