Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRHB9SR)

• DOT Name: Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2)
• Synonyms: NHERF-2; NHE3 kinase A regulatory protein E3KARP; SRY-interacting protein 1; SIP-1; Sodium-hydrogen exchanger regulatory factor 2; Solute carrier family 9 isoform A3 regulatory factor 2; Tyrosine kinase activator protein 1; TKA-1
• Gene Name: NHERF2
• UniProt ID: NHRF2_HUMAN
• PDB ID: 2D11; 2HE4; 2OCS; 4P0C
• Pfam ID: PF09007 ; PF00595
• Sequence:
  MAAPEPLRPRLCRLVRGEQGYGFHLHGEKGRRGQFIRRVEPGSPAEAAALRAGDRLVEVN
  GVNVEGETHHQVVQRIKAVEGQTRLLVVDQETDEELRRRQLTCTEEMAQRGLPPAHDPWE
  PKPDWAHTGSHSSEAGKKDVSGPLRELRPRLCHLRKGPQGYGFNLHSDKSRPGQYIRSVD
  PGSPAARSGLRAQDRLIEVNGQNVEGLRHAEVVASIKAREDEARLLVVDPETDEHFKRLR
  VTPTEEHVEGPLPSPVTNGTSPAQLNGGSACSSRSDLPGSDKDTEDGSAWKQDPFQESGL
  HLSPTAAEAKEKARAMRVNKRAPQMDWNRKREIFSNF
• 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 cAMP-mediated phosphorylation and inhibition of SLC9A3. May also act as scaffold protein in the nucleus.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Aldosterone-regulated sodium reabsorption (hsa04960)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[1]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[8]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[9]
Ampicillin	DMHWE7P	Approved	Ampicillin increases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Na(+)/H(+) exchange regulatory cofactor NHE-RF2 (NHERF2).	[9]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] 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.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [9] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [10] 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.
• [11] 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.