Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUW3SAX)

• DOT Name: Post-GPI attachment to proteins factor 2 (PGAP2)
• Synonyms: FGF receptor-activating protein 1
• Gene Name: PGAP2
• Related Disease:
  Intellectual disability, autosomal dominant 40
  Advanced cancer
  Beckwith-Wiedemann syndrome
  Bone osteosarcoma
  Cleft lip/palate
  Hyperphosphatasia with intellectual disability syndrome 3
  Intellectual disability
  Osteosarcoma
  Hyperphosphatasia-intellectual disability syndrome
• UniProt ID: PGAP2_HUMAN
• Pfam ID: PF10277
• Sequence:
  MYQVPLPLDRDGTLVRLRFTMVALVTVCCPLVAFLFCILWSLLFHFKETTATHCGVPNYL
  PSVSSAIGGEVPQRYVWRFCIGLHSAPRFLVAFAYWNHYLSCTSPCSCYRPLCRLNFGLN
  VVENLALLVLTYVSSSEDFTIHENAFIVFIASSLGHMLLTCILWRLTKKHTVSQEDRKSY
  SWKQRLFIINFISFFSALAVYFRHNMYCEAGVYTIFAILEYTVVLTNMAFHMTAWWDFGN
  KELLITSQPEEKRF
• Function: Involved in the lipid remodeling steps of GPI-anchor maturation. Required for stable expression of GPI-anchored proteins at the cell surface.
• Tissue Specificity: Ubiquitously expressed, with highest levels in testis and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[3]
Hyperphosphatasia with intellectual disability syndrome 3	DISN934M	Strong	Autosomal recessive	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Hyperphosphatasia-intellectual disability syndrome	DISQJ9HK	Supportive	Autosomal recessive	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[12]
Marinol	DM70IK5	Approved	Marinol increases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[17]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Post-GPI attachment to proteins factor 2 (PGAP2).	[18]

2 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 Post-GPI attachment to proteins factor 2 (PGAP2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Post-GPI attachment to proteins factor 2 (PGAP2).	[16]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Human FRAG1 encodes a novel membrane-spanning protein that localizes to chromosome 11p15.5, a region of frequent loss of heterozygosity in cancer.Genomics. 1999 Nov 15;62(1):59-66. doi: 10.1006/geno.1999.5980.
• [3] Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival.Elife. 2019 Jun 24;8:e45248. doi: 10.7554/eLife.45248.
• [4] Late transcription and simultaneous replication of simian adenovirus 7 DNA as revealed by spreading lytically infected cell cultures. J Gen Virol. 1979 Mar;42(3):443-56. doi: 10.1099/0022-1317-42-3-443.
• [5] A novel mutation in PGAP2 gene causes developmental delay, intellectual disability, epilepsy and microcephaly in consanguineous Saudi family.J Neurol Sci. 2016 Dec 15;371:121-125. doi: 10.1016/j.jns.2016.10.027. Epub 2016 Oct 18.
• [6] PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome. Am J Hum Genet. 2013 Apr 4;92(4):584-9. doi: 10.1016/j.ajhg.2013.03.011.
• [7] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] 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.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.