Notch Signaling
Pathway Description:
Notch receptor signaling is one of several evolutionarily conserved signaling pathways fundamental to metazoan development. The Notch pathway mediates regulation of a diverse array of cell fate decisions through juxtacrine signaling among adjacent cells. In mammals, members of the Delta-like (DLL1, DLL3, DLL4) and the Jagged (JAG1, JAG2) families function as ligands that activate Notch signaling receptors. Notch receptors are single-pass trans-membrane proteins composed of functional extracellular (NECD), transmembrane, and intracellular domains. Notch proteins are processed in the ER and Golgi, producing a glycosylated, Ca2+-stabilized heterodimer composed of two cleavage products derived from full-length Notch protein. Upon ligand binding, the NECD is removed through cleavage by an ADAM metalloprotease TNF-α converting enzyme (TACE); a second cleavage event mediated by γ-secretase releases the Notch intracellular domain (NICD). This NICD fragment translocates to the nucleus and associates with a CSL (CBF1/Su(H)/Lag-1) family transcription factor complex, resulting in the activation of downstream targets, including Myc and HES family genes. The NECD remains bound to the ligand, and both proteins undergo endocytosis and likely recycling/degradation within the ligand-bearing cell. Notch receptor mutations are common in adult T cell acute lymphoblastic leukemia and lymphoma, while mutant Notch receptor and ligands are implicated in several disorders, including Alagille syndrome and an autosomal dominant form of cerebral arteriopathy (CADASIL).
Selected Reviews:
- Barolo S, Posakony JW (2002) Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Genes Dev. 16(10), 1167–81.
- Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 7(9), 678–89.
- Grabher C, von Boehmer H, Look AT (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat. Rev. Cancer 6(5), 347–59.
- Kopan R (2002) Notch: a membrane-bound transcription factor. J. Cell. Sci. 115(Pt 6), 1095–7.
- Louvi A, Artavanis-Tsakonas S (2006) Notch signalling in vertebrate neural development. Nat. Rev. Neurosci. 7(2), 93–102.
CST would like to thank Gregory Hurlbut, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, for contributing to this diagram.
created June 2006 • revised November 2006
