Development - Notch Signaling Pathway

Notch Signaling Pathway

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].

References:

1. Bolos V, Grego-Bessa J, de la Pompa JL
   Notch signaling in development and cancer. Endocrine reviews 2007 May;28(3):339-63
2. Bruckner K, Perez L, Clausen H, Cohen S
   Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 2000 Jul 27;406(6794):411-5
3. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD
   SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function. Molecular and cellular biology 2000 Apr;20(7):2400-10
4. Mumm JS, Kopan R
   Notch signaling: from the outside in. Developmental biology 2000 Dec 15;228(2):151-65
5. Kopan R
   Notch: a membrane-bound transcription factor. Journal of cell science 2002 Mar 15;115(Pt 6):1095-7
6. Hsieh JJ, Zhou S, Chen L, Young DB, Hayward SD
   CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proceedings of the National Academy of Sciences of the United States of America 1999 Jan 5;96(1):23-8
7. Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T
   A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes & development 1998 Aug 1;12(15):2269-77
8. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Hayward SD
   A role for SKIP in EBNA2 activation of CBF1-repressed promoters. Journal of virology 2000 Feb;74(4):1939-47
9. Gupta-Rossi N, Le Bail O, Gonen H, Brou C, Logeat F, Six E, Ciechanover A, Israel A
   Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. The Journal of biological chemistry 2001 Sep 14;276(37):34371-8