The Notch signalling pathway is crucial for cell fate decisions during embryogenesis and in fully developed organisms. Notch receptors (4 genes in humans) are single pass trans-membrane proteins that interact with membrane-bound endogenous peptide ligands from the Delta/Serrate/LAG-2 (DSL) family. Receptor-ligand engagement can occur in trans (between adjacent cells) or cis (on the same cell). Notch-ligand complexes formed in trans are endocytosed by the ligand-expressing cell, followed by protease-mediated cleavages that free the intracellular fragment of Notch (NICD) to translocate to the nucleus where it participates in the assembly of transcriptional activation complexes. Cis-formed complexes are inhibitory in function and act to restrict the spread of Notch activity.

Aberrant Notch signalling is implicated in a number of human hereditary and acquired diseases, including cancers [7,13,15,18], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [3,11].

* Key recommended reading is highlighted with an asterisk

Arumugam TV, Baik SH, Balaganapathy P, Sobey CG, Mattson MP, Jo DG. (2018) Notch signaling and neuronal death in stroke. Prog Neurobiol, 165-167: 103-116. [PMID:29574014]

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]

* Fabbro D, Bauer M, Murone M, Lehal R. (2020) Notch Inhibition in Cancer: Challenges and Opportunities. Chimia (Aarau), 74 (10): 779-783. [PMID:33115560]

* Moore G, Annett S, McClements L, Robson T. (2020) Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells, 9 (6). DOI: 10.3390/cells9061503 [PMID:32575680]

* 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. Astudillo L, Da Silva TG, Wang Z, Han X, Jin K, VanWye J, Zhu X, Weaver K, Oashi T, Lopes PE et al.. (2016) The Small Molecule IMR-1 Inhibits the Notch Transcriptional Activation Complex to Suppress Tumorigenesis. Cancer Res, 76 (12): 3593-603. [PMID:27197169]

3. Fabbro D, Bauer M, Murone M, Lehal R. (2020) Notch Inhibition in Cancer: Challenges and Opportunities. Chimia (Aarau), 74 (10): 779-783. [PMID:33115560]

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. Gurney Al, Hoey TC, Bruhns MF, Axelrod FT. (2014) Notch1 receptor binding agents and methods of use thereof. Patent number: US20140011271A1. Assignee: Oncomed Pharmaceuticals. Priority date: 08/07/2008. Publication date: 09/01/2014.

6. Gurney AL, Hoey TC, van der Horst ETH, Sato AK, Liu YC, Bruhns MF, Lewicki JA. (2012) Antibodies to notch receptors. Patent number: US8226943 B2. Assignee: Oncomed Pharmaceuticals, Inc.. Priority date: 08/07/2008. Publication date: 24/07/2012.

7. 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]

8. 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]

9. Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J. (1997) Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor. Mol Cell Biol, 17 (10): 6057-67. [PMID:9315665]

10. 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]

11. Moore G, Annett S, McClements L, Robson T. (2020) Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells, 9 (6). DOI: 10.3390/cells9061503 [PMID:32575680]

12. 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]

13. 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]

14. 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]

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. 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]

19. 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]

Thiruma V. Arumugam Department of Physiology Yong Loo Lin School Medicine National University of Singapore Singapore Singapore Christopher Sobey Department of Pharmacology Monash University Clayton, Victoria, 3800 Australia