The canonocal Notch signalling pathway has four type I transmembrane Notch receptors (Notch1-4) and five ligands (DLL1, 2 and 3, and Jagged 1-2). Each member of this highly conserved receptor family plays a unique role in cell-fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [2]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor-ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by γ-secretase is required for downstream signalling and Notch-induced transcriptional modulation [3,10,14,21]. This is why γ-secretase inhibitors can be used to downregulate Notch signalling and explains their anti-cancer action. One such small molecule is RO4929097 [7], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [18].

Aberrant Notch signalling is implicated in a number of human cancers [5,11,15,19], with demcizumab and tarextumab identified as antibody inhibitors of ligand:receptor binding [12].

* Key recommended reading is highlighted with an asterisk

* Borggrefe T, Lauth M, Zwijsen A, Huylebroeck D, Oswald F, Giaimo BD. (2016) The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFβ/BMP and hypoxia pathways. Biochim. Biophys. Acta, 1863 (2): 303-13. [PMID:26592459]

* Cheng YL, Choi Y, Sobey CG, Arumugam TV, Jo DG. (2015) Emerging roles of the γ-secretase-notch axis in inflammation. Pharmacol. Ther., 147: 80-90. [PMID:25448038]

* Palmer WH, Deng WM. (2015) Ligand-Independent Mechanisms of Notch Activity. Trends Cell Biol., 25 (11): 697-707. [PMID:26437585]

* Previs RA, Coleman RL, Harris AL, Sood AK. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin. Cancer Res., 21 (5): 955-61. [PMID:25388163]

* Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, Yang SX, Ivy SP. (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol, 12 (8): 445-64. [PMID:25850553]

1. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J et al.. (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science, 333 (6046): 1154-7. [PMID:21798897]

2. Al-Hussaini H, Subramanyam D, Reedijk M, Sridhar SS. (2011) Notch signaling pathway as a therapeutic target in breast cancer. Mol. Cancer Ther., 10 (1): 9-15. [PMID:20971825]

3. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ et al.. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature, 398 (6727): 518-22. [PMID:10206645]

4. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature, 437 (7056): 270-4. [PMID:16025100]

5. Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I, Devgan V, Lieb J, Raffoul W, Hohl D et al.. (2007) Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev., 21 (5): 562-77. [PMID:17344417]

6. Lehmann BD, Pietenpol JA, Tan AR. (2015) Triple-negative breast cancer: molecular subtypes and new targets for therapy. Am Soc Clin Oncol Educ Book, 35: e31-9. [PMID:25993190]

7. Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H et al.. (2009) Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res., 69 (19): 7672-80. [PMID:19773430]

8. McBride KL, Riley MF, Zender GA, Fitzgerald-Butt SM, Towbin JA, Belmont JW, Cole SE. (2008) NOTCH1 mutations in individuals with left ventricular outflow tract malformations reduce ligand-induced signaling. Hum. Mol. Genet., 17 (18): 2886-93. [PMID:18593716]

9. Nagamatsu I, Onishi H, Matsushita S, Kubo M, Kai M, Imaizumi A, Nakano K, Hattori M, Oda Y, Tanaka M et al.. (2014) NOTCH4 is a potential therapeutic target for triple-negative breast cancer. Anticancer Res., 34 (1): 69-80. [PMID:24403446]

10. Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. (2006) Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell, 124 (5): 973-83. [PMID:16530044]

11. 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. [PMID:24651013]

12. Previs RA, Coleman RL, Harris AL, Sood AK. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin. Cancer Res., 21 (5): 955-61. [PMID:25388163]

13. Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, Escaramis G, Jares P, Beà S, González-Díaz M et al.. (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature, 475 (7354): 101-5. [PMID:21642962]

14. Schroeter EH, Kisslinger JA, Kopan R. (1998) Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature, 393 (6683): 382-6. [PMID:9620803]

15. Sjölund J, Johansson M, Manna S, Norin C, Pietras A, Beckman S, Nilsson E, Ljungberg B, Axelson H. (2008) Suppression of renal cell carcinoma growth by inhibition of Notch signaling in vitro and in vivo. J. Clin. Invest., 118 (1): 217-28. [PMID:18079963]

16. Stittrich AB, Lehman A, Bodian DL, Ashworth J, Zong Z, Li H, Lam P, Khromykh A, Iyer RK, Vockley JG et al.. (2014) Mutations in NOTCH1 cause Adams-Oliver syndrome. Am. J. Hum. Genet., 95 (3): 275-84. [PMID:25132448]

17. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A et al.. (2011) The mutational landscape of head and neck squamous cell carcinoma. Science, 333 (6046): 1157-60. [PMID:21798893]

18. Strosberg JR, Yeatman T, Weber J, Coppola D, Schell MJ, Han G, Almhanna K, Kim R, Valone T, Jump H et al.. (2012) A phase II study of RO4929097 in metastatic colorectal cancer. Eur. J. Cancer, 48 (7): 997-1003. [PMID:22445247]

19. Vilimas T, Mascarenhas J, Palomero T, Mandal M, Buonamici S, Meng F, Thompson B, Spaulding C, Macaroun S, Alegre ML et al.. (2007) Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat. Med., 13 (1): 70-7. [PMID:17173050]

20. Weng AP, Ferrando AA, Lee W, Morris 4th JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 306 (5694): 269-71. [PMID:15472075]

21. Wilson JJ, Kovall RA. (2006) Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell, 124 (5): 985-96. [PMID:16530045]