Notch Signaling

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Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

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 juxtacrine signaling among adjacent cells by which a diverse array of cell fate decisions in neuronal, cardiac, immune, and endocrine development are regulated. 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 to enable ligand binding. In mammals, members of the Delta-like (DLL1, DLL3, DLL4) and the Jagged (JAG1, JAG2) families, which are located in the signal-sending cell, serve as ligands for 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, γ-secretase (also involved in Alzheimer’s disease) releases the NICD from the TM (S3 cleavage), which translocates to the nucleus where it associates with the CSL (CBF1/Su(H)/Lag-1) family transcription factor complex, resulting in subsequent activation of the canonical Notch target genes Myc, p21 and HES-family members. The Notch signaling pathway has spurred interest for pharmacological intervention due to its connection to human disease. Importantly, Notch receptor activating mutations leading to nuclear accumulation 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 CADASIL, an autosomal dominant form of cerebral arteriopathy.

Selected Reviews:

• Aster JC, Pear WS, Blacklow SC (2008) Notch signaling in leukemia. Annu Rev Pathol 3, 587–613.
• High FA, Epstein JA (2008) The multifaceted role of Notch in cardiac development and disease. Nat. Rev. Genet. 9(1), 49–61.
• Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137(2), 216–33.
• Lathia JD, Mattson MP, Cheng A (2008) Notch: from neural development to neurological disorders. J. Neurochem. 107(6), 1471–81.
• Radtke F, Fasnacht N, Macdonald HR (2010) Notch signaling in the immune system. Immunity 32(1), 14–27.
• Tien AC, Rajan A, Bellen HJ (2009) A Notch updated. J. Cell Biol. 184(5), 621–9.
• Wilson CW, Chuang PT (2006) New "hogs" in Hedgehog transport and signal reception. Cell 125(3), 435–8.
• Yuan JS, Kousis PC, Suliman S, Visan I, Guidos CJ (2010) Functions of notch signaling in the immune system: consensus and controversies. Annu. Rev. Immunol. 28, 343–65.

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