Intracellular domain of Notch

Fig. 12.2. Model of Notch signalling. The Notch protein is a ligand activated transmembrane receptor which is subject to proteolysis of the intracellular domain upon ligand binding. The nature of the protease involved is still a matter of debate. The proteolytically released intranceUu-lar domain of Notch (NICD) translocates into the nucleus where it interacts with a family of transcription factors, the CSL proteins, resulting in a change in transcription of target genes.

O-fucose is an important modification that mediates cell-cell interactions and leads to intracellular signaling events. Fucose is linked to either serine or threonine found in the consensus sequence C2XXGGS/TC3. The best-characterized modification sites are in the EGF domain of Notch (113). 0-Fuc is added by protein O-fucosyltransferase (0-FucT-I) and may be either a standalone modification or further extended. If extended. 

Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. 2001. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J. Biol. Chem. 276 40288-92... 

De Strooper, B., Annaert, W. G., Cupers, P. et al. A presenilin-1 -dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398 518-522,1999. 

Figure 5 Proteolytic processing and signaling of the Notch receptor. In the ER, Notch is cleaved at SI by a furin-like protease to produce a stable heterodimeric receptor that is trafficked to the cell surface. Interaction with ligands such as the proteins Delta and Jagged triggers a shedding of the ectodomain by membrane-tethered metalloprotease-mediated cleavage at S2. The remnant then is cleaved at least twice, at the S3 and S4 sites, to release the Notch counterpart of Ap (Np) and the intracellular domain (NICD). The latter translocates to the nucleus where it interacts with transcription factors to influence gene expression relevant to cell differentiation.

De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, et al. A presenilin-1-dependent y-secretase-like protease mediates release of Notch intracellular domain. Nature 1999 398 518-522. Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature 1998 393 382-386. 

Schroeter, E.H., Kisslinger, J.A., and Kopan, R. (1998). Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain [see comments]. Nature 595 382-386. 

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