Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT97F1TU)

• DOT Name: Gamma-secretase subunit APH-1A (APH1A)
• Synonyms: APH-1a; Aph-1alpha; Presenilin-stabilization factor
• Gene Name: APH1A
• Related Disease:
  Acne vulgaris
  Adenocarcinoma
  Advanced cancer
  Alzheimer disease
  Amyloidosis
  Androgen insensitivity syndrome
  Bacterial meningitis
  Breast neoplasm
  Cerebral palsy
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Epithelial neoplasm
  Kidney cancer
  Kidney neoplasm
  Neoplasm
  Neoplasm with perivascular epithelioid cell differentiation
  Neuroblastoma
  Obesity
  Papillary renal cell carcinoma
  Pituitary gland disorder
  Renal carcinoma
  Stroke
  Renal cell carcinoma
  Amyotrophic lateral sclerosis
  Castration-resistant prostate carcinoma
• UniProt ID: APH1A_HUMAN
• PDB ID: 5A63; 5FN2; 5FN3; 5FN4; 5FN5; 6IDF; 6IYC; 6LQG; 6LR4; 7C9I; 7D8X; 7Y5T; 7Y5X; 7Y5Z
• Pfam ID: PF06105
• Sequence:
  MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
  DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
  SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
  ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
  RSLLCRRQEDSRVMVYSALRIPPED
• Function: Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Required for normal gamma-secretase assembly. The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable).
• Tissue Specificity: Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.
• 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

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acne vulgaris	DISKW8PI	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[5]
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[6]
Bacterial meningitis	DISRP9SL	Strong	Biomarker	[7]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[8]
Cerebral palsy	DIS82ODL	Strong	Altered Expression	[9]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[11]
Epithelial neoplasm	DIS0T594	Strong	Biomarker	[11]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[12]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Neoplasm with perivascular epithelioid cell differentiation	DIS8V0NT	Strong	Biomarker	[15]
Neuroblastoma	DISVZBI4	Strong	Genetic Variation	[15]
Obesity	DIS47Y1K	Strong	Altered Expression	[16]
Papillary renal cell carcinoma	DIS25HBV	Strong	Genetic Variation	[17]
Pituitary gland disorder	DIS7XB48	Strong	Altered Expression	[18]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[12]
Stroke	DISX6UHX	Strong	Biomarker	[19]
Renal cell carcinoma	DISQZ2X8	Disputed	Genetic Variation	[11]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[20]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[21]

9 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 Gamma-secretase subunit APH-1A (APH1A).	[22]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Gamma-secretase subunit APH-1A (APH1A).	[24]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Gamma-secretase subunit APH-1A (APH1A).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Gamma-secretase subunit APH-1A (APH1A).	[26]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Gamma-secretase subunit APH-1A (APH1A).	[27]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Gamma-secretase subunit APH-1A (APH1A).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gamma-secretase subunit APH-1A (APH1A).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Gamma-secretase subunit APH-1A (APH1A).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Gamma-secretase subunit APH-1A (APH1A).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Gamma-secretase subunit APH-1A (APH1A).	[23]

References

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• [17] Fusion of splicing factor genes PSF and NonO (p54nrb) to the TFE3 gene in papillary renal cell carcinoma.Oncogene. 1997 Oct;15(18):2233-9. doi: 10.1038/sj.onc.1201394.
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• [21] Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF.Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):10461-10466. doi: 10.1073/pnas.1706076114. Epub 2017 Sep 11.
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• [25] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
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• [27] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [28] 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.
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• [30] 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.
• [31] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.