Notch homolog 1 translocation-associated (NOTCH1) is synthesized as NOTCH1 precursor, which is cleaved by Furin to NOTCH1 receptor form. NOTCH1 receptor is activated by Jagged [1]. O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase (fringe)-dependent glycosylation of NOTCH1 receptor increases its ability to bind Delta-like (DLL) [2], but prevents NOTCH1 receptor activation by Jagged. After activation NOTCH1 receptor is cleaved by Presenilin 1 and ADAM metallopeptidase domain 17 (ADAM17). Intracellular domain of NOTCH1 (NOTCH1 (NICD)) is transported to nucleus and participates in Recombination signal binding protein for immunoglobulin kappa J region (RBP-J kappa (CBF1))-mediated transcription [1].

RBP-J kappa (CBF1) can act as transcription repressor or activator dependent on protein complex, which it recruits to DNA [3], [4], [5]. RBP-J kappa (CBF1) acts as gene repressor in a complex with co-repressors Nuclear receptor co-repressor 2 (SMRT)/Nuclear receptor co-repressor 1 (N-CoR)/ Histone deacetylase 1 (HDAC1) [4], [6] or CBF1 interacting corepressor (CIR)/ Sin3A-associated protein 30kDa (SAP30)/ Histone deacetylase 2 (HDAC2) [4], [6]. HDAC participates in histone deacetylation, which prevents transcription. SMRT and CIR function as linkers between HDAC and RBP-J kappa (CBF1) via direct binding of linker protein SNW domain containing 1 (SKIP) [3], [6], [7], [8]. NOTCH1 (NICD) binding to SKIP competes with SMRT [3] and, possibly, CIR [4]. NOTCH1 (NICD) recruits Mastermind-like 1 (MAML1), which facilitates E1A binding protein p300 (p300) recruitment. The last one in turn facilitates p300/CBP-associated factor (PCAF) recruitment. Complex MAML1/p300/PCAF acts as histone acetylase and assist chromatin remodeling. NOTCH1 (NICD) competition with RBP-J kappa (CBF1) corepressors determines positive regulation of transcription by NOTCH1 (NICD).

Notch signaling is shut off by ubiquitin-proteasome-mediated degradation of NOTCH1 (NICD) by F-box and WD repeat domain containing 7 (FBXW7) after a nuclear phosphorylation event [9].

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