Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMB586Q)

• DOT Name: Protein numb homolog (NUMB)
• Synonyms: h-Numb; Protein S171
• Gene Name: NUMB
• Related Disease:
  Acute myelogenous leukaemia
  Myelodysplastic syndrome
  Advanced cancer
  Alzheimer disease
  Breast carcinoma
  Breast neoplasm
  Cervical Intraepithelial neoplasia
  Colonic neoplasm
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Hepatitis C virus infection
  Intrahepatic cholangiocarcinoma
  Liver cirrhosis
  Lung cancer
  Lung carcinoma
  Malignant glioma
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Bipolar disorder
  Breast cancer
  Cone-rod dystrophy
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Adult glioblastoma
  Carcinoma of liver and intrahepatic biliary tract
  Cervical cancer
  Cervical carcinoma
  Coronary heart disease
  Liver cancer
  Melanoma
  Nasopharyngeal carcinoma
  Rheumatoid arthritis
• UniProt ID: NUMB_HUMAN
• PDB ID: 5NJJ; 5NJK
• Pfam ID: PF06311 ; PF00640
• Sequence:
  MNKLRQSFRRKKDVYVPEASRPHQWQTDEEGVRTGKCSFPVKYLGHVEVDESRGMHICED
  AVKRLKAERKFFKGFFGKTGKKAVKAVLWVSADGLRVVDEKTKDLIVDQTIEKVSFCAPD
  RNFDRAFSYICRDGTTRRWICHCFMAVKDTGERLSHAVGCAFAACLERKQKREKECGVTA
  TFDASRTTFTREGSFRVTTATEQAEREEIMKQMQDAKKAETDKIVVGSSVAPGNTAPSPS
  SPTSPTSDATTSLEMNNPHAIPRRHAPIEQLARQGSFRGFPALSQKMSPFKRQLSLRINE
  LPSTMQRKTDFPIKNAVPEVEGEAESISSLCSQITNAFSTPEDPFSSAPMTKPVTVVAPQ
  SPTFQANGTDSAFHVLAKPAHTALAPVAMPVRETNPWAHAPDAANKEIAATCSGTEWGQS
  SGAASPGLFQAGHRRTPSEADRWLEEVSKSVRAQQPQASAAPLQPVLQPPPPTAISQPAS
  PFQGNAFLTSQPVPVGVVPALQPAFVPAQSYPVANGMPYPAPNVPVVGITPSQMVANVFG
  TAGHPQAAHPHQSPSLVRQQTFPHYEASSATTSPFFKPPAQHLNGSAAFNGVDDGRLASA
  DRHTEVPTGTCPVDPFEAQWAALENKSKQRTNPSPTNPFSSDLQKTFEIEL
• Function: Regulates clathrin-mediated receptor endocytosis. Plays a role in the process of neurogenesis. Required throughout embryonic neurogenesis to maintain neural progenitor cells, also called radial glial cells (RGCs), by allowing their daughter cells to choose progenitor over neuronal cell fate. Not required for the proliferation of neural progenitor cells before the onset of neurogenesis. Also involved postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity. May also mediate local repair of brain ventricular wall damage.
• KEGG Pathway: Notch sig.ling pathway (hsa04330)
• Reactome Pathway:
  Recycling pathway of L1 (R-HSA-437239)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Hedgehog 'on' state (R-HSA-5632684)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Myelodysplastic syndrome	DISYHNUI	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Biomarker	[2]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[9]
Hepatitis C virus infection	DISQ0M8R	Strong	Posttranslational Modification	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[2]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Malignant glioma	DISFXKOV	Strong	Biomarker	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[14]
Prostate cancer	DISF190Y	Strong	Altered Expression	[15]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[15]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[16]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[4]
Cone-rod dystrophy	DISY9RWN	moderate	Biomarker	[17]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[18]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[19]
Adult glioblastoma	DISVP4LU	Disputed	Altered Expression	[9]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Posttranslational Modification	[20]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[21]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[21]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[22]
Liver cancer	DISDE4BI	Limited	Posttranslational Modification	[20]
Melanoma	DIS1RRCY	Limited	Biomarker	[23]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[24]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[25]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein numb homolog (NUMB).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein numb homolog (NUMB).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein numb homolog (NUMB).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein numb homolog (NUMB).	[30]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein numb homolog (NUMB).	[31]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Protein numb homolog (NUMB).	[32]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of Protein numb homolog (NUMB).	[32]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Protein numb homolog (NUMB).	[33]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Protein numb homolog (NUMB).	[34]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein numb homolog (NUMB).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein numb homolog (NUMB).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein numb homolog (NUMB).	[37]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein numb homolog (NUMB).	[38]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Protein numb homolog (NUMB).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein numb homolog (NUMB).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein numb homolog (NUMB).	[29]

References

• [1] Distinct expression profiles of MSI2 and NUMB genes in myelodysplastic syndromes and acute myeloid leukemia patients.Leuk Res. 2012 Oct;36(10):1300-3. doi: 10.1016/j.leukres.2012.06.010. Epub 2012 Jul 9.
• [2] Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy.Oncotarget. 2018 Apr 10;9(27):18916-18928. doi: 10.18632/oncotarget.24828. eCollection 2018 Apr 10.
• [3] Numb endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner: implications for Alzheimer disease pathogenesis.J Biol Chem. 2008 Sep 12;283(37):25492-25502. doi: 10.1074/jbc.M802072200. Epub 2008 Jul 2.
• [4] Cytokeratin 19 (KRT19) has a Role in the Reprogramming of Cancer Stem Cell-Like Cells to Less Aggressive and More Drug-Sensitive Cells.Int J Mol Sci. 2018 May 9;19(5):1423. doi: 10.3390/ijms19051423.
• [5] NUMB controls p53 tumour suppressor activity.Nature. 2008 Jan 3;451(7174):76-80. doi: 10.1038/nature06412.
• [6] Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer.Mol Cell Biol. 2011 Jan;31(1):138-50. doi: 10.1128/MCB.00709-10. Epub 2010 Nov 1.
• [7] Suppression of cancer stemness by upregulating Ligand-of-Numb protein X1 in colorectal carcinoma.PLoS One. 2017 Nov 30;12(11):e0188665. doi: 10.1371/journal.pone.0188665. eCollection 2017.
• [8] Increased Numb protein expression predicts poor clinical outcomes in esophageal squamous cell carcinoma patients.Cancer Biol Ther. 2018 Jan 2;19(1):34-41. doi: 10.1080/15384047.2016.1276131. Epub 2017 Dec 18.
• [9] HMGA1 negatively regulates NUMB expression at transcriptional and post transcriptional level in glioblastoma stem cells.Cell Cycle. 2019 Jul;18(13):1446-1457. doi: 10.1080/15384101.2019.1618541. Epub 2019 May 22.
• [10] AP-2-associated protein kinase 1 and cyclin G-associated kinase regulate hepatitis C virus entry and are potential drug targets.J Virol. 2015 Apr;89(8):4387-404. doi: 10.1128/JVI.02705-14. Epub 2015 Feb 4.
• [11] Deletion of Ser-171 causes inactivation, proteasome-mediated degradation and complete deficiency of human transaldolase.Biochem J. 2004 Sep 1;382(Pt 2):725-31. doi: 10.1042/BJ20040413.
• [12] RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation.Mol Cell. 2013 Dec 12;52(5):720-33. doi: 10.1016/j.molcel.2013.11.010.
• [13] NUMB does not impair growth and differentiation status of experimental gliomas.Exp Cell Res. 2011 Dec 10;317(20):2864-73. doi: 10.1016/j.yexcr.2011.09.002. Epub 2011 Sep 12.
• [14] Numb Gene Enhances Radiation Sensitivity of Nonsmall Cell Lung Cancer Stem Cells.Cancer Biother Radiopharm. 2016 Jun;31(5):180-8. doi: 10.1089/cbr.2016.2053.
• [15] Numb(-/low) Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling.Clin Cancer Res. 2017 Nov 1;23(21):6744-6756. doi: 10.1158/1078-0432.CCR-17-0913. Epub 2017 Jul 27.
• [16] Genome-wide association of mood-incongruent psychotic bipolar disorder.Transl Psychiatry. 2012 Oct 23;2(10):e180. doi: 10.1038/tp.2012.106.
• [17] Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.
• [18] Musashi2 promotes the development and progression of pancreatic cancer by down-regulating Numb protein.Oncotarget. 2017 Feb 28;8(9):14359-14373. doi: 10.18632/oncotarget.8736. Epub 2016 Apr 15.
• [19] Alternative splicing of NUMB, APP and VEGFA as the features of pancreatic ductal carcinoma.Int J Clin Exp Pathol. 2015 Jun 1;8(6):6181-91. eCollection 2015.
• [20] NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer.Hepatology. 2015 Nov;62(5):1466-79. doi: 10.1002/hep.27987. Epub 2015 Aug 28.
• [21] NUMB is a break of WNT-Notch signaling cycle.Int J Mol Med. 2006 Sep;18(3):517-21.
• [22] The association of cholesterol absorption gene Numb polymorphism with Coronary Artery Disease among Han Chinese and Uighur Chinese in Xinjiang, China.Lipids Health Dis. 2015 Sep 29;14:120. doi: 10.1186/s12944-015-0102-6.
• [23] miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization.Mol Cancer Res. 2016 Jun;14(6):548-62. doi: 10.1158/1541-7786.MCR-15-0425-T.
• [24] Inhibition of the Numb/Notch signaling pathway increases radiation sensitivity in human nasopharyngeal carcinoma cells.Kaohsiung J Med Sci. 2019 Aug;35(8):474-485. doi: 10.1002/kjm2.12087. Epub 2019 Jul 4.
• [25] Expression analysis of Notch-related molecules in peripheral blood T helper cells of patients with rheumatoid arthritis.Scand J Rheumatol. 2010;39(1):26-32. doi: 10.3109/03009740903124424.
• [26] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [27] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [28] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [31] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [32] Modulation of notch signaling pathway to prevent H2O2/menadione-induced SK-N-MC cells death by EUK134. Cell Mol Neurobiol. 2014 Oct;34(7):1037-45. doi: 10.1007/s10571-014-0079-0. Epub 2014 Jul 9.
• [33] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [34] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [35] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [36] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [37] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [38] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.