Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT03870U)

• DOT Name: Pleckstrin homology domain-containing family A member 8 (PLEKHA8)
• Synonyms: PH domain-containing family A member 8; Phosphatidylinositol-four-phosphate adapter protein 2; FAPP-2; Phosphoinositol 4-phosphate adapter protein 2; hFAPP2; Serologically defined breast cancer antigen NY-BR-86
• Gene Name: PLEKHA8
• Related Disease:
  Advanced cancer
  Neoplasm
  Colon cancer
  Colon carcinoma
• UniProt ID: PKHA8_HUMAN
• PDB ID: 5KDI
• Pfam ID: PF08718 ; PF00169
• Sequence:
  MEGVLYKWTNYLSGWQPRWFLLCGGILSYYDSPEDAWKGCKGSIQMAVCEIQVHSVDNTR
  MDLIIPGEQYFYLKARSVAERQRWLVALGSAKACLTDSRTQKEKEFAENTENLKTKMSEL
  RLYCDLLVQQVDKTKEVTTTGVSNSEEGIDVGTLLKSTCNTFLKTLEECMQIANAAFTSE
  LLYRTPPGSPQLAMLKSSKMKHPIIPIHNSLERQMELSTCENGSLNMEINGEEEILMKNK
  NSLYLKSAEIDCSISSEENTDDNITVQGEIRKEDGMENLKNHDNNLTQSGSDSSCSPECL
  WEEGKEVIPTFFSTMNTSFSDIELLEDSGIPTEAFLASCYAVVPVLDKLGPTVFAPVKMD
  LVGNIKKVNQKYITNKEEFTTLQKIVLHEVEADVAQVRNSATEALLWLKRGLKFLKGFLT
  EVKNGEKDIQTALNNAYGKTLRQHHGWVVRGVFALALRAAPSYEDFVAALTVKEGDHQKE
  AFSIGMQRDLSLYLPAMEKQLAILDTLYEVHGLESDEVV
• Function: Cargo transport protein that is required for apical transport from the Golgi complex. Transports AQP2 from the trans-Golgi network (TGN) to sites of AQP2 phosphorylation. Mediates the non-vesicular transport of glucosylceramide (GlcCer) from the trans-Golgi network (TGN) to the plasma membrane and plays a pivotal role in the synthesis of complex glycosphingolipids. Binding of both phosphatidylinositol 4-phosphate (PIP) and ARF1 are essential for the GlcCer transfer ability. Also required for primary cilium formation, possibly by being involved in the transport of raft lipids to the apical membrane, and for membrane tubulation.
• Tissue Specificity: Expressed in kidney cell lines.
• Reactome Pathway: Synthesis of PIPs at the plasma membrane (R-HSA-1660499)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Colon cancer	DISVC52G	moderate	Biomarker	[2]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Pleckstrin homology domain-containing family A member 8 (PLEKHA8).	[8]

References

• [1] FAPP2 gene downregulation increases tumor cell sensitivity to Fas-induced apoptosis.Biochem Biophys Res Commun. 2009 May 29;383(2):167-71. doi: 10.1016/j.bbrc.2009.03.126. Epub 2009 Mar 31.
• [2] FAPP2 promotes tumor cell growth in human colon cancer through activation of Wnt signaling.Exp Cell Res. 2019 Jan 1;374(1):12-18. doi: 10.1016/j.yexcr.2018.11.002. Epub 2018 Nov 5.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [7] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [8] 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.
• [9] 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.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.