Pathway Map Details

Development_Notch Signaling Pathway

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Object list (links open in MetaCore):

c-Rel (NF-kB subunit), HDAC2, NOTCH1 receptor, SKIP (Ski-interacting protein), PCAF, MAML1, Cullin 1, NOTCH1 receptor = NOTCH1 (NEXT), NOTCH1 precursor, p63, NOTCH1 receptor = NOTCH1 (NEXT), TLE, None, ADAM17, SAP30, FBXW7, Manic fringe glycosyltransferase, DLL4, HES1, gamma-Secretase complex, GCN5, MYOD, p300, NOTCH1 receptor, Histone deacetylase class I, HEY1, Jagged1, NOTCH1 (NEXT), CIR, Histone H4, NFKBIA, NOTCH1 (NICD), SMRT, N-CoR, Histone H3, Radical fringe, Jagged2, p73, HEY2, RBP-J kappa (CBF1), Lunatic fringe, Furin, DLL1, None, HDAC1


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 ) [6], [4] or CBF1 interacting corepressor ( CIR )/ Sin3A-associated protein 30kDa ( SAP30 )/ Histone deacetylase 2 ( HDAC2 ) [6], [4]. 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 ) [7], [6], [8], [3]. 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].


  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