Notch Signaling

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• Reviews
• Pathway Key
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Pathway Description:

Notch signaling is an evolutionarily conserved pathway in multicellular organisms that regulates cell-fate determination during development and in stem cells. The Notch pathway mediates regulation of a diverse array of cell fate decisions in neuronal, cardiac and endocrine development through juxtacrine signaling among adjacent cells. Notch receptors are single-pass trans-membrane proteins composed of functional extracellular (NECD), transmembrane (TM), and intracellular domains. ER and Golgi processing of notch receptors in the signal-receiving cell results in cleavage and produces a glycosylated, Ca2+-stabilized heterodimer composed of NECD non-covalently attached to the TM-NICD inserted in the membrane (S1 cleavage). This processed receptor is then translocated to the plasma membrane for binding to ligand. In mammals, members of the Delta-like (DLL1, DLL3, DLL4) and the Jagged (JAG1, JAG2) families, which are located in the signal-sending cell, function as ligands that activate Notch signaling receptors. Upon ligand binding, the NECD is cleaved away (S2 cleavage) from the TM-NICD domain by TACE (ADAM metalloprotease TNF-α converting enzyme). The NECD remains bound to the ligand and this complex undergoes endocytosis and recycling/degradation within the signal-sending cell. In the signal-receiving cell, a third cleavage event mediated by γ-secretase (also involved in Alzheimer’s disease) releases the NICD from the TM (S3 cleavage), which translocates to the nucleus and associates with the CSL (CBF1/Su(H)/Lag-1) family transcription factor complex, resulting in subsequent activation of the notch target genes Myc, p21 and HES family members. Strikingly, notch receptor activating mutations leading to nuclear accumulaton of NICD are common in adult T-cell acute lymphoblastic leukemia and lymphoma. In addition, loss-of-function Notch receptor and ligand mutations are implicated in several disorders, including Alagille syndrome and an autosomal dominant form of cerebral arteriopathy (CADASIL), which have collectively spurred the interest for pharmacological pathway intervention in human disease.

Selected Reviews:

• Aster JC, Pear WS, Blacklow SC (2008) Notch signaling in leukemia. Annu Rev Pathol 3, 587–613.
• Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 7(9), 678–89.
• Fiúza UM, Arias AM (2007) Cell and molecular biology of Notch. J. Endocrinol. 194(3), 459–74.
• High FA, Epstein JA (2008) The multifaceted role of Notch in cardiac development and disease. Nat. Rev. Genet. 9(1), 49–61.
• Louvi A, Artavanis-Tsakonas S (2006) Notch signalling in vertebrate neural development. Nat. Rev. Neurosci. 7(2), 93–102.
• Tanigaki K, Honjo T (2007) Regulation of lymphocyte development by Notch signaling. Nat. Immunol. 8(5), 451–6.

CST would like to thank Dr. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, for contributing to this diagram.