Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development Notch Signaling Pathway


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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].