Development Notch Signaling Pathway

Notch Signaling Pathway

Notch homolog 1 translocation-associated ( NOTCH1 ) is synthesized as NOTCH1precursor, which is cleaved by Furin to NOTCH1 receptor form.NOTCH1 receptor is activated by Jagged [1]. O-fucosylpeptide3-beta-N-acetylglucosaminyltransferase ( fringe )-dependent glycosylation ofNOTCH1 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 1and ADAM metallopeptidase domain 17 ( ADAM17 ). Intracellular domain ofNOTCH1 ( NOTCH1 (NICD) ) is transported to nucleus and participatesin Recombination signal binding protein for immunoglobulin kappa J region ( RBP-Jkappa (CBF1) )-mediated transcription [1].

RBP-J kappa (CBF1) can act as transcription repressor or activator dependent onprotein complex, which it recruits to DNA [3], [4], [5]. RBP-J kappa (CBF1) acts as gene repressor in a complex withco-repressors Nuclear receptor co-repressor 2 ( SMRT )/Nuclear receptorco-repressor 1 ( N-CoR )/ Histone deacetylase 1 ( HDAC1 ) [6],[4] or CBF1 interacting corepressor ( CIR )/ Sin3A-associated protein30kDa ( SAP30 )/ Histone deacetylase 2 ( HDAC2 ) [6], [4]. HDAC participates in histone deacetylation, which preventstranscription. SMRT and CIR function as linkers between HDAC andRBP-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-like1 ( 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 acetylaseand 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 nuclearphosphorylation event [9].

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