Pathway Map Details

Development_NOTCH1-mediated pathway for NF-KB activity modulation

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Object list (links open in MetaCore):

MEKK1(MAP3K1), Histone deacetylase class I, IRAK1/2, TRAF6, MAML1, NFKBIA, Histone H3, PCAF, NOTCH1 receptor = NOTCH1 (NEXT), ADAM17, NOTCH1 (NICD), IL-1 alpha, p300, NOTCH1 receptor, gamma-Secretase complex, HDAC2, IKK (cat), NOTCH1(NEXT) = NOTCH1(NICD), NF-kB, SKIP (Ski-interacting protein), SAP30, IL-1RI, CIR, N-CoR, DLL1, RBP-J kappa (CBF1), NOTCH1 (NEXT), NF-kB, NFKBIA, NIK(MAP3K14), c-Rel (NF-kB subunit), SMRT, HDAC1, Jagged1, I-kB, Histone H4


NOTCH1-mediated pathway for NF-KB activity modulation

Interleukin 1 ( IL-1 ) activates Nuclear factor of kappa light polypeptide gene enhancer in B-cells ( NF-KB ) via Interleukin-1 receptor-associated kinase ( IRAK ) and Mitogen-activated protein kinase kinase kinase 1 ( MEKK1(MAP3K1) )-dependent inhibition of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor ( I-kB ) [1], [2]. V-rel reticuloendotheliosis viral oncogene homolog ( c-Rel (NF-kB subunit) ) can trigger Notch homolog 1 translocation-associated ( NOTCH1 receptor ) signaling pathway by inducing expression of Jagged1, ligand for Notch receptors [3], [4]. NOTCH1 receptor activated by Jagged1 or Delta-like 1 ( DLL1 ) is cleaved by ADAM metallopeptidase domain 17 ( ADAM17 ) and Presenilin1 to intracellular domain of NOTCH1 ( NOTCH1 (NICD) ). NOTCH1 (NICD) is transported to nucleus and participates in recombination signal binding protein for immunoglobulin kappa J region ( RBP-J kappa (CBF1) )-mediated transcription [5], [4].

RBP-J kappa (CBF1) can act as transcription repressor or activator, depending on protein complex, which it recruits to DNA [6], [7], [8]. 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 ) [9], [7] or CBF1 interacting corepressor ( CIR )/ Sin3A-associated protein 30kDa ( SAP30 )/ Histone deacetylase 2 ( HDAC2 ) [9], [7]. HDAC participates in histone deacetylation, which prevents transcription. SMRT and CIR function act as linkers between HDAC and RBP-J kappa (CBF1) via direct binding of linker protein SNW domain containing 1 ( SKIP ) [10], [9], [11], [6]. Intracellular domain of Notch homolog 1 translocation-associated ( NOTCH1 (NICD) ) binding to SKIP competes with SMRT [6] and, possibly, CIR [7]. NOTCH1 (NICD) recruits Mastermind-like 1 ( MAML1 ), which facilitates E1A binding protein p300 ( p300 ) recruitment. The latter 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).

This pathway enables NOTCH1 (NICD) activation of transcription of Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha ( NFKBIA ) and thus lowers NF-KB activity [4].


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