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notch receptor 1

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 2861

Nomenclature: notch receptor 1

Family: Notch receptors

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 2555 9q34.3 NOTCH1 notch receptor 1
Mouse 1 2531 2 18.91 cM Notch1 notch 1
Rat 1 2531 3p13 Notch1 notch receptor 1
Previous and Unofficial Names Click here for help
notch 1 | Notch (Drosophila) homolog 1 (translocation-associated) | TAN1
Database Links Click here for help
Alphafold
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
IMR-1 Small molecule or natural product Hs Binding 5.0 pKd 1
pKd 5.0 (Kd 1.1x10-5 M) [1]
Description: Binding affinity for hNOTCH1 intracellular domain determined by SPR.
Inhibitor Comments
CB-103 is a small molecule that binds to the cleaved NOTCH1 receptor intracellular domain (NICD) that translocates to the nucleus and is a component of the functional nuclear NOTCH transcriptional activation complex. By inhibiting NOTCH-mediated transcriptional activation, CB-103 brings about anti-tumour effects in cancer cells that are driven by dominant active NICD.
Antibodies
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Antibody Sp. Action Value Parameter Reference
brontictuzumab Peptide Hs Binding 8.4 pKd 5
pKd 8.4 (Kd 4.33x10-9 M) [5]
Immunopharmacology Comments
NOTCH1 and its ligand Delta-like 4 (DLL4) play a dominant role in mediating the effects of Notch signaling in T cells during Graft-versus-host disease (GvHD). Anti-NOTCH1 or anti-DLL4 antibodies controlled GvHD [8]. Anti-NOTCH1 was associated with dose-limiting toxicity; anti-DLL4 was not.

Activating mutations in NOTCH1 are one of the most frequent somatic alterations detected in chronic lymphocytic leukemia (CLL), and such mutations are associated with poor prognosis [6-7,9]. The mutations found in CLL generally affect the PEST domain of the receptor, are not ongogenic in isolation and are NOTCH ligand dependent. Different NOTCH1 mutations are found in T-acute lymphoblastic leukemia (T-ALL) [2], and these are more likely to lead to constitutive, ligand-independent NOTCH pathway activation.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0002437 inflammatory response to antigenic stimulus IEA
Immuno Process:  Tissue repair
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0042246 tissue regeneration IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0032633 interleukin-4 production IEA
General Comments
NOTCH1 is a single-pass transmembrane receptor protein that controls T-cell differentiation. Gain-of-function mutations in NOTCH1 are present in >50% of human T-cell acute lymphoblastic leukemias (T-ALL) [3-4].

References

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1. 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]

2. Belver L, Ferrando A. (2016) The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer, 16 (8): 494-507. [PMID:27451956]

3. Bhanushali AA, Babu S, Thangapandi VR, Pillai R, Chheda P, Das BR. (2010) Mutations in the HD and PEST domain of Notch-1 receptor in T-cell acute lymphoblastic leukemia: report of novel mutations from Indian population. Oncol Res, 19 (2): 99-104. [PMID:21302811]

4. Grabher C, von Boehmer H, Look AT. (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer, 6 (5): 347-59. [PMID:16612405]

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. 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]

7. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, Marasca R, Laurenti L, Bruscaggin A, Cerri M et al.. (2012) Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood, 119 (2): 521-9. [PMID:22077063]

8. Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J, Shan GT, Radojcic V, Friedman A, Gridley T, Shelton A et al.. (2013) Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest, 123 (4): 1590-604. [PMID:23454750]

9. Villamor N, Conde L, Martínez-Trillos A, Cazorla M, Navarro A, Beà S, López C, Colomer D, Pinyol M, Aymerich M et al.. (2013) NOTCH1 mutations identify a genetic subgroup of chronic lymphocytic leukemia patients with high risk of transformation and poor outcome. Leukemia, 27 (5): 1100-6. [PMID:23295735]

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