Overview of Notch Signaling

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Notch signaling is involved in the development of every system in the body. This pathway is one of only a few signaling pathways that are used over and over in a variety of developmental processes, in both adult and embryonic tissues. Notch signaling is one mechanism by which cells influence the developmental outcomes of their neighbors. It requires cell-cell contact and mediates a vast array of binary cell fate decisions resulting in proliferation, survival, self-renewal, or differentiation. The effects of this signaling are difficult to characterize because they are manifest in a contextual manner. Notch can have a variety of outcomes depending on cell type, microenvironment, and external factors.

In mammalian systems there are four known Notch receptors: Notch 1, 2, 3, and 4; and five different Notch ligands: Delta-like (DLL) 1, 3, and 4, and Jagged (JAG) 1 and 2. DLLs are small molecules that can signal in trans (intercellular) or cis (intracellular). The cell expressing Notch ligand (DLL or Jagged) is called the Signaling Cell. Notch itself is a heterodimer expressed on the surface of the Receiving Cell. The extracellular (EC) domain is noncovalently bound to the transmembrane (TM)/intracellular (IC) domains. Upon activation, the EC domain disengages from the TM/IC domains and is internalized by the signaling cell along with the bound ligand. The TM/IC domain then undergoes two cleavages by ADAM10 or ADAM17 and the γ-secretase complex respectively. These cleavages release the IC domain which translocates to the nucleus. There it binds to and displaces repressors CBF-1 and CSL (RBP-jκ). MAML is recruited to Notch, which in turn recruits other factors forming the Notch Transcription Complex (NTC).

Dysregulation of Notch signaling and other developmental pathways (e.g. Wnt and Hedgehog) plays an important role in the generation of a wide range of human cancers. Most human cancers are thought to contain a population of cells with stem cell-like properties, Cancer Stem Cells (CSCs). Self-renewal and cell fate determination of CSCs are regulated by both intrinsic and extrinsic pathways, including Notch. For example, in CSCs Notch signaling can result in asymmetric cell division producing a self-renewing daughter cell and a differentiating daughter cell. Increased Notch signaling tends to enhance self-renewal of CSCs. CSCs are resistant to chemotherapeutic agents and radiation, which can lead to treatment failure and relapse.

Notch can trigger EMT events via regulation of factors such as Snail and Slug. Epithelial (Endothelial)-to-Mesenchymal Transition (EMT) is a process by which mature differentiated epithelial or endothelial cells can de-differentiate to a less mature mesenchymal phenotype. An epithelial/endothelial pattern of gene expression (phenotype) is associated with sensitivity to chemotherapeutic agents. Thus EMT promotes resistance to a broad range of chemotherapeutic agents. Notch signaling also modifies the tumor microenvironment by regulating expression of cytokines and other factors, including the induction of Tregs. High levels of expression of the Notch ligand Jagged further results in increased Notch signaling and promotes metastasis.

 

 

Detection of human Notch1 by WB of immunoprecipitates from HeLa lysate

Detection of human Notch1 by WB of immunoprecipitates from HeLa lysate. Antibodies: Rabbit anti-Notch1 (A301-894A and A301-895A).

Detection of Phospho RelA (S468) in FFPE sections of human ovarian carcinoma by IHC

Detection of Phospho RelA (S468) in FFPE sections of human ovarian carcinoma by IHC. Mock phosphatase treated section (left) and calf intestinal phosphatase-treated section (right). Antibody: Rabbit anti- Phospho RelA (S468) (A302-064A). Detection: HRP-conjugated goat anti-rabbit IgG (A120-501P), DAB.

Below is the current listing of Bethyl antibodies involved in Notch signaling pathway research:

 

References

1. Espinoza I, Pochampally R, Xing F, Watabe K, Miele L. 2013. Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. OncoTargets Ther. Sept 6;6:1249-1259.

2. Capaccione KM, Pine SR. 2013. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. Jul;34(7):1420-1430.

3. Koch U, Lehal R, Radtke F. 2013. Stem cells living with a Notch. Development. Feb;140(4): 689-704.

Contributed by Steve Anderson, Ph.D.