Notch Signaling

Pathway Description:

Notch signaling is an evolutionarily conserved pathway in multicellular organisms that regulates cell-fate determination during development and maintains adult tissue homeostasis. The Notch pathway mediates juxtacrine cellular signaling wherein both the signal sending and receiving cells are affected through ligand-receptor crosstalk by which an array of cell fate decisions in neuronal, cardiac, immune, and endocrine development are regulated. Notch receptors are single-pass transmembrane proteins composed of functional extracellular (NECD), transmembrane (TM), and intracellular (NICD) domains. Notch receptors are processed in the ER and Golgi within the signal-receiving cell through cleavage and glycosylation, generating a Ca2+-stabilized heterodimer composed of NECD noncovalently attached to the TM-NICD inserted in the membrane (S1 cleavage). The processed receptor is then endosome-transported to the plasma membrane to enable ligand binding in a manner regulated by Deltex and inhibited by NUMB. In mammalian signal-sending cells, members of the Delta-like (DLL1, DLL3, DLL4) and the Jagged (JAG1, JAG2) families serve as ligands for Notch signaling receptors. Upon ligand binding, the NECD is cleaved away (S2 cleavage) from the TM-NICD domain by TACE (TNF-α ADAM metalloprotease converting enzyme). The NECD remains bound to the ligand and this complex undergoes endocytosis/recycling within the signal-sending cell in a manner dependent on ubiquitination by Mib. 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 (CBF1/Su(H)/Lag-1) transcription factor complex, resulting in subsequent activation of the canonical Notch target genes: Myc, p21, and the HES-family members. The Notch signaling pathway has spurred interest for pharmacological intervention due to its connection to human disease. Importantly, researchers have found 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:

• Ables JL, Breunig JJ, Eisch AJ, Rakic P (2011) Not(ch) just development: Notch signalling in the adult brain. Nat. Rev. Neurosci. 12(5), 269–83.
• Andersson ER, Lendahl U (2014) Therapeutic modulation of Notch signalling--are we there yet? Nat Rev Drug Discov 13(5), 357–78.
• Aster JC, Blacklow SC, Pear WS (2011) Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. J. Pathol. 223(2), 262–73.
• Bai G, Pfaff SL (2011) Protease regulation: the Yin and Yang of neural development and disease. Neuron 72(1), 9–21.
• de la Pompa JL, Epstein JA (2012) Coordinating tissue interactions: Notch signaling in cardiac development and disease. Dev. Cell 22(2), 244–54.
• Ntziachristos P, Lim JS, Sage J, Aifantis I (2014) From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25(3), 318–34.
• Ranganathan P, Weaver KL, Capobianco AJ (2011) Notch signalling in solid tumours: a little bit of everything but not all the time. Nat. Rev. Cancer 11(5), 338–51.
• Weinmaster G, Fischer JA (2011) Notch ligand ubiquitylation: what is it good for? Dev. Cell 21(1), 134–44.
• 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.