Details of Drug Off-Target (DOT)

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

• DOT Name: Numb-like protein (NUMBL)
• Synonyms: Numb-related protein; Numb-R
• Gene Name: NUMBL
• Related Disease:
  Neoplasm
  Advanced cancer
  Glioma
  Neuroblastoma
  Schizophrenia
  Lung carcinoma
  Prostate carcinoma
• UniProt ID: NUMBL_HUMAN
• PDB ID: 3F0W
• Pfam ID: PF06311 ; PF00640
• Sequence:
  MSRSAAASGGPRRPERHLPPAPCGAPGPPETCRTEPDGAGTMNKLRQSLRRRKPAYVPEA
  SRPHQWQADEDAVRKGTCSFPVRYLGHVEVEESRGMHVCEDAVKKLKAMGRKSVKSVLWV
  SADGLRVVDDKTKDLLVDQTIEKVSFCAPDRNLDKAFSYICRDGTTRRWICHCFLALKDS
  GERLSHAVGCAFAACLERKQRREKECGVTAAFDASRTSFAREGSFRLSGGGRPAEREAPD
  KKKAEAAAAPTVAPGPAQPGHVSPTPATTSPGEKGEAGTPVAAGTTAAAIPRRHAPLEQL
  VRQGSFRGFPALSQKNSPFKRQLSLRLNELPSTLQRRTDFQVKGTVPEMEPPGAGDSDSI
  NALCTQISSSFASAGAPAPGPPPATTGTSAWGEPSVPPAAAFQPGHKRTPSEAERWLEEV
  SQVAKAQQQQQQQQQQQQQQQQQQQQAASVAPVPTMPPALQPFPAPVGPFDAAPAQVAVF
  LPPPHMQPPFVPAYPGLGYPPMPRVPVVGITPSQMVANAFCSAAQLQPQPATLLGKAGAF
  PPPAIPSAPGSQARPRPNGAPWPPEPAPAPAPELDPFEAQWAALEGKATVEKPSNPFSGD
  LQKTFEIEL
• Function: 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 embryonic neurogenesis. Also required postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity. Negative regulator of NF-kappa-B signaling pathway. The inhibition of NF-kappa-B activation is mediated at least in part, by preventing MAP3K7IP2 to interact with polyubiquitin chains of TRAF6 and RIPK1 and by stimulating the 'Lys-48'-linked polyubiquitination and degradation of TRAF6 in cortical neurons.
• KEGG Pathway: Notch sig.ling pathway (hsa04330)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[2]
Glioma	DIS5RPEH	Strong	Genetic Variation	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[6]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Numb-like protein (NUMBL).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Numb-like protein (NUMBL).	[11]

2 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 Numb-like protein (NUMBL).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Numb-like protein (NUMBL).	[10]

References

• [1] NUMB and NUMBL differences in gene regulation.Oncotarget. 2018 Jan 11;9(10):9219-9234. doi: 10.18632/oncotarget.24186. eCollection 2018 Feb 6.
• [2] Changes in DNA methylation of tandem DNA repeats are different from interspersed repeats in cancer.Int J Cancer. 2009 Aug 1;125(3):723-9. doi: 10.1002/ijc.24384.
• [3] Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors.Cancer Genet Cytogenet. 2008 Oct 15;186(2):103-9. doi: 10.1016/j.cancergencyto.2008.07.003.
• [4] Distillation of the clinical algorithm improves prognosis by multi-task deep learning in high-risk Neuroblastoma.PLoS One. 2018 Dec 7;13(12):e0208924. doi: 10.1371/journal.pone.0208924. eCollection 2018.
• [5] Analysis of coding-polymorphisms in NOTCH-related genes reveals NUMBL poly-glutamine repeat to be associated with schizophrenia in Brazilian and Danish subjects.Schizophr Res. 2006 Dec;88(1-3):275-82. doi: 10.1016/j.schres.2006.06.036. Epub 2006 Aug 8.
• [6] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [7] Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.EBioMedicine. 2016 Aug;10:150-63. doi: 10.1016/j.ebiom.2016.07.022. Epub 2016 Jul 20.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] 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.
• [10] 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.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.