Details of Drug Off-Target (DOT)

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

• DOT Name: Gamma-secretase subunit APH-1B (APH1B)
• Synonyms: APH-1b; Aph-1beta; Presenilin-stabilization factor-like
• Gene Name: APH1B
• Related Disease:
  ADan amyloidosis
  Coronary heart disease
  Neurodevelopmental disorder
  Myopia
  Parkinson disease
• UniProt ID: APH1B_HUMAN
• Pfam ID: PF06105
• Sequence:
  MTAAVFFGCAFIAFGPALALYVFTIATEPLRIIFLIAGAFFWLVSLLISSLVWFMARVII
  DNKDGPTQKYLLIFGAFVSVYIQEMFRFAYYKLLKKASEGLKSINPGETAPSMRLLAYVS
  GLGFGIMSGVFSFVNTLSDSLGPGTVGIHGDSPQFFLYSAFMTLVIILLHVFWGIVFFDG
  CEKKKWGILLIVLLTHLLVSAQTFISSYYGINLASAFIILVLMGTWAFLAAGGSCRSLKL
  CLLCQDKNFLLYNQRSR
• Function: Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.
• Tissue Specificity: Weakly or not expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, colon, skeletal muscle, heart and brain.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Alzheimer disease (hsa05010)
• Reactome Pathway:
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  NOTCH4 Activation and Transmission of Signal to the Nucleus (R-HSA-9013700)
  Noncanonical activation of NOTCH3 (R-HSA-9017802)
  Amyloid fiber formation (R-HSA-977225)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ADan amyloidosis	DISXF54F	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[2]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[3]
Myopia	DISK5S60	Limited	Genetic Variation	[4]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Gamma-secretase subunit APH-1B (APH1B).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Gamma-secretase subunit APH-1B (APH1B).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Gamma-secretase subunit APH-1B (APH1B).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[11]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Gamma-secretase subunit APH-1B (APH1B).	[8]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Gamma-secretase subunit APH-1B (APH1B).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Gamma-secretase subunit APH-1B (APH1B).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Gamma-secretase subunit APH-1B (APH1B).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Gamma-secretase subunit APH-1B (APH1B).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Gamma-secretase subunit APH-1B (APH1B).	[19]

References

• [1] Deletion of the -secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia.Oncotarget. 2016 Mar 15;7(11):11923-44. doi: 10.18632/oncotarget.7389.
• [2] Male-specific association between a gamma-secretase polymorphism and premature coronary atherosclerosis.PLoS One. 2008;3(11):e3662. doi: 10.1371/journal.pone.0003662. Epub 2008 Nov 6.
• [3] Gene dosage effect on gamma-secretase component Aph-1b in a rat model for neurodevelopmental disorders.Neuron. 2005 Feb 17;45(4):497-503. doi: 10.1016/j.neuron.2004.12.054.
• [4] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [5] Cerebrospinal fluid A42 levels and APP processing pathway genes in Parkinson's disease.Mov Disord. 2015 Jun;30(7):936-44. doi: 10.1002/mds.26172. Epub 2015 Mar 24.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.