Notch Signaling Pathway

As a crucial cell signaling pathway in metazoan development, the Notch signaling pathway controls cell fate decisions in many different tissues in multicellular organisms. The Notch signaling pathway is composed of the Notch receptor, the Notch ligand (DSL protein), the CSL (CBF-1, Suppressor of hairless, a combination of Lag) DNA-binding protein, other effectors, and the regulatory molecule of Notch. In 1917, Morgan discovered the Notch gene in mutant Drosophila, which was named because a partial loss of function in the gene that caused a nick on the edge of the fruit fly. Mammals have four different Notch receptors (Notchl-4) and five Notch ligands (Delta-like 1, 3, 4, Jagged 1 and Jagged 2). The receptor subsequently traffics to the cell surface to interact with its ligands. And ligands are type I transmembrane proteins with a large extracellular domain and a relatively short intracellular domain. The ligand binds to the receptor at the interface between the two signaling cells. This leads to the release of the intracellular portion of the receptor that translocates into the nucleus, and interacts with a transcription factor and coactivators to activate transcription. The Notch extracellular domain undergoes its first proteolytic cleavage (S1) in the Golgi complex by furin-like proteases. This processing is thought to contribute to the net signaling activity by facilitating exocytosis of Notch. Upon ligand–receptor interactions, the ligand–receptor complex becomes endocytosed into the signal sending cell (trans-endocytosis) creating a “pulling force” that leads to a conformational change that promotes receptor activation. This leads to the second (S2) cleavage of the Notch receptor. The second cleavage releases the intracellular domain of Notch, which translocates to the nucleus. In the signal-receiving cell, γ-secretase (also involved in Alzheimer’s disease) releases the NICD from the TM (S3 cleavage), which allows for nuclear translocation where it associates with the CSL family of transcriptional regulators and forms part of a Notch target gene–activating complex. So it can activate the target genes of the basichelix-loop-helix (bHLH) transcriptional repressor family and exert biological effect.

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