Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFK8KDP)

• DOT Name: Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1)
• Synonyms: NHERF-1; Ezrin-radixin-moesin-binding phosphoprotein 50; EBP50; Regulatory cofactor of Na(+)/H(+) exchanger; Sodium-hydrogen exchanger regulatory factor 1; Solute carrier family 9 isoform A3 regulatory factor 1
• Gene Name: NHERF1
• Related Disease:
  Hypophosphatemic nephrolithiasis/osteoporosis 2
  Obsolete dominant hypophosphatemia with nephrolithiasis or osteoporosis
• UniProt ID: NHRF1_HUMAN
• PDB ID: 1G9O; 1GQ4; 1GQ5; 1I92; 1SGH; 2D10; 2JXO; 2KJD; 2KRG; 2M0T; 2M0U; 2M0V; 2OZF; 4JL7; 4LMM; 4MPA; 4N6X; 4PQW; 4Q3H; 6RQR
• Pfam ID: PF09007 ; PF00595
• Sequence:
  MSADAAAGAPLPRLCCLEKGPNGYGFHLHGEKGKLGQYIRLVEPGSPAEKAGLLAGDRLV
  EVNGENVEKETHQQVVSRIRAALNAVRLLVVDPETDEQLQKLGVQVREELLRAQEAPGQA
  EPPAAAEVQGAGNENEPREADKSHPEQRELRPRLCTMKKGPSGYGFNLHSDKSKPGQFIR
  SVDPDSPAEASGLRAQDRIVEVNGVCMEGKQHGDVVSAIRAGGDETKLLVVDRETDEFFK
  KCRVIPSQEHLNGPLPVPFTNGEIQKENSREALAEAALESPRPALVRSASSDTSEELNSQ
  DSPPKQDSTAPSSTSSSDPILDFNISLAMAKERAHQKRSSKRAPQMDWSKKNELFSNL
• Function: Scaffold protein that connects plasma membrane proteins with members of the ezrin/moesin/radixin family and thereby helps to link them to the actin cytoskeleton and to regulate their surface expression. Necessary for recycling of internalized ADRB2. Was first known to play a role in the regulation of the activity and subcellular location of SLC9A3. Necessary for cAMP-mediated phosphorylation and inhibition of SLC9A3. May enhance Wnt signaling. May participate in HTR4 targeting to microvilli. Involved in the regulation of phosphate reabsorption in the renal proximal tubules. Involved in sperm capacitation. May participate in the regulation of the chloride and bicarbonate homeostasis in spermatozoa.
• Tissue Specificity: Detected in liver, kidney, pancreas, prostate, spleen, small intestine and placenta, in particular in the syncytiotrophoblast.
• KEGG Pathway:
  Tight junction (hsa04530)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Pathogenic Escherichia coli infection (hsa05130)
  Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypophosphatemic nephrolithiasis/osteoporosis 2	DISLWE7I	Moderate	Autosomal dominant	[1]
Obsolete dominant hypophosphatemia with nephrolithiasis or osteoporosis	DISGRJU9	Supportive	Autosomal dominant	[2]

22 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 Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[15]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[16]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[17]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[18]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[20]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[5]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF1 (NHERF1).	[23]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] NHERF1 mutations and responsiveness of renal parathyroid hormone. N Engl J Med. 2008 Sep 11;359(11):1128-35. doi: 10.1056/NEJMoa0802836.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [12] 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.
• [13] 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.
• [14] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [15] 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.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [18] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [19] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [22] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [23] 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.
• [24] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.