Notch receptors | Other protein targets | IUPHAR/BPS Guide to PHARMACOLOGY

Notch receptors C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Aberrant Notch signalling is implicated in a number of human cancers [7,12,14,17], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [3,10].

Targets

notch receptor 1 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

2861

Nomenclature

notch receptor 1

Previous and unofficial names

notch 1 | Notch (Drosophila) homolog 1 (translocation-associated) | TAN1

Genes

NOTCH1 (Hs), Notch1 (Mm), Notch1 (Rn)

Ensembl ID

ENSG00000148400 (Hs), ENSMUSG00000026923 (Mm), ENSRNOG00000019322 (Rn)

UniProtKB AC

P46531 (Hs), Q01705 (Mm), Q07008 (Rn)

Inhibitors

IMR-1 (Binding) pK_d 5.0 [2]

Antibodies

brontictuzumab (Binding) pK_d 8.4 [5]

Comment

Various types of activating and inactivating NOTCH1 mutations have been reported to be associated with human diseases, for example: aortic valve disease [4,9], Adams-Oliver syndrome 5 [15], T-cell acute lymphoblastic leukemia (T-ALL) [18], chronic lymphocytic leukemia (CLL) [13] and head and neck squamous cell carcinoma [1,16].

notch receptor 2 C Show summary »« Hide summary More detailed page go icon to follow link

notch receptor 3 C Show summary »« Hide summary More detailed page go icon to follow link

notch receptor 4 C Show summary »« Hide summary

Target Id	2862
Nomenclature	notch receptor 4
Previous and unofficial names	INT3 \| Notch homolog 4 (Drosophila) \| notch 4
Genes	NOTCH4 (Hs), Notch4 (Mm), Notch4 (Rn)
Ensembl ID	ENSG00000204301 (Hs), ENSMUSG00000015468 (Mm), ENSRNOG00000000442 (Rn)
UniProtKB AC	Q99466 (Hs), P31695 (Mm)
Comment	Notch receptor 4 is a potential therapeutic molecular target for triple-negative breast cancer [8,11].

References

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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. 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]

10. 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]

11. 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]

12. 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]

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. 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]

15. 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]

16. 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]

17. 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]

18. 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]

NC-IUPHAR subcommittee and family contributors

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Buneman OP, Faccenda E, Harding SD, Spedding M, Cidlowski JA, Fabbro D, Davenport AP, Striessnig J, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets. Br J Pharmacol. 180 Suppl 2:S1-22.