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The Notch Signaling Pathway

                            

The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.  It consists of notch receptors and notch ligands, as well as intracellular proteins transmitting the notch signal to the cell's nucleus. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptors are a single-pass transmembrane receptor protein. The notch signaling pathway has four unique characteristics.

First, notch ligands are also transmembrane proteins.  Therefore, the receptor is normally triggered only from direct cell-to-cell contact. Such cellular interaction is a key mechanism for cell-interdependant growth and differentiation. In this manner, if one cell expresses a given trait, this may be switched off in neighbor cells by the intercellular notch signal. In this way, groups of cells influence one another to make large structures. The notch ligands are members of the DSL (i.e. Delta-Serrate-LAG2) family of proteins.

Second, modification of the notch extracellular domain plays crucial and diverse roles in notch signaling.  The notch extracellular domain is composed primarily of small EGF-like repeats. Notch 1, for example, has 36 of these repeats. Each EGF-like repeat is composed of approximately 40 amino acids, and its structure is defined largely by six conserved cysteine residues that form three conserved disulfide bonds. Each EGF-like repeat can be modified by O-linked glycans at specific sites. Such modification is absolutely necessary for notch function.

Third, notch may inhibit signaling through one ligand while simultaneously potentiate signaling through another. This is called “fringe effect”. In mammals, the O-linked glycans can be elongated by different types of  N-Acetylglucosaminyltransferase called Fringe. By catalyzing orderly addition of certain sugar molecules to the O-linked glycans, these enzymes are responsible for the "fringe effect" on notch signaling. The exact mechanism is not clearly understood.

Fourth, binding of ligand promotes two proteolytic processing events. Once the notch extracellular domain interacts with a ligand, an ADAM-family metalloprotease called TACE (Tumor Necrosis Factor Alpha Converting Enzyme) cleaves the notch protein just outside the membrane.  This releases the extracellular portion of notch, which continues to interact with the ligand. The ligand plus the notch extracellular domain is then endocytosed by the ligand-expressing cell. There may be signaling effects in the ligand-expressing cell after endocytosis; this part of notch signaling is a topic of active research. After the cleavage of extracellular portion of notch, the intracellular domain is also liberated through a proteolytic event and can enter the nucleus to engage other DNA-binding proteins and regulate gene expression.

Notch signaling has been implicated in the development of the heart, pancreas, intestine and bone. It is particularly important in regulating crucial cell communication events between endocardium and myocardium during both the formation of the valve primordial and ventricular development and differentiation. It is also involved in timely cell lineage specification of both endocrine and exocrine pancreas, and cell-fate decision in mammary glands.  Notch signaling is dysregulated in many cancers,  and faulty notch signaling is implicated in many diseases including T-cell acute lymphoblastic leukemia, multiple sclerosis, Tetralogy of Fallot, Alagille syndrome, and many other disease states.




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