Notch Signaling Pathways

Click on the buttons below to highlight different stages of Notch regulation.

Mind Bomb 1
Mind Bomb 1
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Epsin
Epsin
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Clathrin
Clathrin
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Picalm
Picalm
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Dynamin
Dynamin
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Notch
Notch
Notch
Notch
NICD
NICD
NICD
NICD
DSL Ligand
DSL Ligand
Notch
Notch
gamma-
Secretase
Complex
gamma-
Secretase
Complex
NOV/CCN3
NOV/CCN3
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Contactin-1
Contactin-1
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Contactin-6
Contactin-6
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DLK-1
DLK-1
DNER
DNER
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MAGP-2
MAGP-2
Netrin-1
Netrin-1
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Thrombospondin-2
Thrombospondin-2
beta-Catenin
beta-Catenin
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Furin
Furin
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MFNG,
MFNG,
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RFNG,
RFNG,
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LFNG
LFNG
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Extracellular
Space
Extracellular
Space
Cytoplasm
Cytoplasm
Bcl-2
Bcl-2
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IKK
IKK
NF kappa B
NF kappa B
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PI 3-K/Akt/TOR
PI 3-K/Akt/TOR
POFUT1
POFUT1
gamma-
Secretase
Complex
gamma-
Secretase
Complex
Proteasome
Proteasome
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FBXW7
FBXW7
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SKIP
SKIP
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EHMT1/2
EHMT1/2
Histone 3, 4
Histone 3, 4
Histone 3, 4
Histone 3, 4
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CSL/RBPj
CSL/RBPj
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CSL/RBPj
CSL/RBPj
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SKIP
SKIP
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NRARP
NRARP
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RUNX
RUNX
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TACC3
TACC3
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Histone
Acetyltransferases
Histone
Acetyltransferases
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MAML
MAML
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CDK8
CDK8
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DYRK1A
DYRK1A
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Casein
Kinase 2
Casein
Kinase 2
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NLK
NLK
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NICD Positive
Regulators
NICD Positive
Regulators
LSD1
LSD1
Bcl-6
Bcl-6
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Bend6
Bend6
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CtBP1
CtBP1
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CIR
CIR
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NCOR
NCOR
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NKAP
NKAP
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SAP30
SAP30
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Sharp/Mint
Sharp/Mint
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HDAC1
HDAC1
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HDAC2
HDAC2
Sirtuin 1
Sirtuin 1
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Numb
Numb
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Thrombospondin-4
Thrombospondin-4
Endosome
Endosome
Endosome
Endosome
Trans-
Activation
Trans-
Activation
Non-Canonical
Ligands:
Non-Canonical
Ligands:
Non-Canonical
Signaling
Non-Canonical
Signaling
Notch
Pre-processing
Notch
Pre-processing
Transcriptional
Corepressors/Linkers:
Transcriptional
Corepressors/Linkers:
Histone
Deacetylases:
Histone
Deacetylases:
Transcriptionally
Repressed
Transcriptionally
Repressed
Transcriptionally
Active
Transcriptionally
Active
Canonical
Signaling
Canonical
Signaling
NICD
Degradation
NICD
Degradation
Golgi
Golgi
Endoplasmic
Reticulum
Endoplasmic
Reticulum
Notch Target Genes
Notch Target Genes
O-fucose
O-fucose
N-acetylglucosamine
N-acetylglucosamine
Notch Target
Genes
Notch Target
Genes
Ligand/NECD
Endocytosis
Ligand/NECD
Endocytosis
NICD
NICD
NECD
NECD
Recycling
Recycling
Lysosomal
Degradation
Lysosomal
Degradation
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alpha-Adaptin
alpha-Adaptin
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HES-1
HES-1
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HEY-1
HEY-1
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Myc
Myc
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Bcl-2
Bcl-2
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Cyclin D1
Cyclin D1
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Nucleus
Nucleus
Lysosomal
Degradation
Lysosomal
Degradation
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TACE/
ADAM17
TACE/
ADAM17
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NICD
NICD
Cleavage at the
Plasma Membrane
or Endosome
Cleavage at the
Plasma Membrane
or Endosome

Overview of Notch Signaling Pathways

The Notch family of receptors includes Notch-1, -2, -3, and -4 are highly conserved proteins with a wide range of physiological roles including regulating cell fate, proliferation, angiogenesis, cell survival, and the immune response. Like many other proteins associated with these processes, aberrant Notch activity is reported to have complex and context-dependent effects on tumorigenesis. Upon translation, Notch undergoes several pre-processing steps during its transport to the membrane. These include the addition of O-fucose by O-fucosyltransferase 1 (POFUT1) in the endoplasmic reticulum and, in the Golgi, the addition of N-acetylglucosamine by any of three N-acetylglucosaminetransferases that in vertebrates include Lunatic Fringe (LFNG), Manic Fringe (MFNG), and Radical Fringe (RFNG). Also in the Golgi, Notch is cleaved by Furin to produce a heterodimer consisting of the Notch intracellular domain (NICD) and the Notch extracellular domain (NECD). The heterodimer is then transported to the membrane where it exists as a single pass transmembrane protein. Notch is thought to be in a cycling state that includes endocytosis and re-insertion into the membrane or it may be targeted for lysosomal degradation.

Notch is activated by a unique process that includes ligand binding and multistep proteolytic processing. Invertebrate, Notch ligands include Delta, Serrate, and Lag2 (DSL), while their DSL counterparts in mammals include Delta-like (DLL)-1, -3, -4, Jagged 1, and Jagged 2. Like Notch, DSL ligands are single pass transmembrane receptors and typical Notch activation includes direct cell-cell interaction (trans-activation). Subsequent to binding Notch, the intracellular domain of the Notch ligand is ubiquitinated via the E3 ligase Mind Bomb-1. This initiates endocytosis of the Notch ligand/NECD complex into the ligand-expressing cell. Common endocytic factors have been implicated in this process including Clathrin, Dynamin, Epsin, and Picalm. The mechanical forces generated by these endocytosis-related events may be important for the next steps in the Notch pathway that include sequential proteolytic cleavage of Notch. Notch is first cleaved by TACE/ADAM17 and then the gamma-Secretase complex that includes Presenilin, PSENEN/PEN-2, APH1, and Nicastrin. Whether gamma-Secretase cleavage occurs at the membrane or the endosomal compartment is still a matter of investigation. After its cleavage, the NICD is released into the cytosol and translocated to the nucleus.

Notch activity is primarily dependent on its ability to regulate gene transcription. Recombination Signal Binding Protein for Immunoglobulin Kappa J Region (RBPj) plays a crucial role in Notch-mediated gene transcription. RBPj is also known as CBF-1, or CSL based on its mammalian (CBF-1), Drosophila (Suppressor of Hairless), and C. elegans (Lag-2) orthologs. In the absence of Notch activation, CSL/RBPj acts as a transcriptional repressor in complex with a growing list of co-repressors, linker proteins, and enzymes such as histone deacetylases (HDACs). In the nucleus the NICD displaces transcriptional repressors and forms a complex with CSL/RBPj and Mastermind-like (MAML). MAML recruits transcriptional co-activators, such as the histone acetyltransferase p300, forming a Notch activator complex that culminates in the transcription of Notch target genes. The number of proteins associated with regulating the activator complex continues to grow. There are kinases that can directly phosphorylate and positively or negatively regulate the NICD. In addition, a range of DNA-binding factors and proteins that directly interact with the NICD exists that can either promote or inhibit transcription depending on the context. Turnover of the NICD is high and phosphorylation by CDK8 promotes recognition by the E3 ligase FBW7, resulting in NICD ubiquitination and proteasomal degradation. There appears to be a complex equilibrium in place, and the balance between of the opposing regulators that dictate the overall level of Notch activity.

Binding of Notch by DSL ligands and transcriptional activation involving CSL/RBPj is considered the canonical Notch pathway. However, descriptions of non-canonical signaling continue to be described. Several non-canonical Notch ligands have been identified that have varied effects including the inhibition or activation of the Notch pathways. In addition, it is evident that there is crosstalk between Notch and other signaling pathways, including Akt/mTOR, NF kappa B, Wnt/beta-Catenin, and others.

To learn more, please visit our Notch Pathway Research Area.