Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT34DCAP)

• DOT Name: NEDD4 family-interacting protein 2 (NDFIP2)
• Synonyms: NEDD4 WW domain-binding protein 5A; Putative MAPK-activating protein PM04/PM05/PM06/PM07; Putative NF-kappa-B-activating protein 413
• Gene Name: NDFIP2
• Related Disease: High blood pressure
• UniProt ID: NFIP2_HUMAN
• Sequence:
  MARRRSQRVCASGPSMLNSARGAPELLRGTATNAEVSAAAAGATGSEELPPGDRGCRNGG
  GRGPAATTSSTGVAVGAEHGEDSLSRKPDPEPGRMDHHQPGTGRYQVLLNEEDNSESSAI
  EQPPTSNPAPQIVQAASSAPALETDSSPPPYSSITVEVPTTSDTEVYGEFYPVPPPYSVA
  TSLPTYDEAEKAKAAAMAAAAAETSQRIQEEECPPRDDFSDADQLRVGNDGIFMLAFFMA
  FIFNWLGFCLSFCITNTIAGRYGAICGFGLSLIKWILIVRFSDYFTGYFNGQYWLWWIFL
  VLGLLLFFRGFVNYLKVRNMSESMAAAHRTRYFFLL
• Function: Activates HECT domain-containing E3 ubiquitin-protein ligases, including ITCH, NEDD4, NEDD4L, SMURF2, WWP1 and WWP2, and consequently modulates the stability of their targets. As a result, may control many cellular processes. Recruits ITCH, NEDD4 and SMURF2 to endosomal membranes. Negatively regulates KCNH2 potassium channel activity by decreasing its cell-surface expression and interfering with channel maturation through recruitment of NEDD4L to the Golgi apparatus and multivesicular body where it mediates KCNH2 degradation. May modulate EGFR signaling. Together with NDFIP1, limits the cytokine signaling and expansion of effector Th2 T-cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-mediated ubiquitination.
• Tissue Specificity: Expressed in brain, lung, heart, skeletal muscle, kidney, liver and placenta.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Strong	Genetic Variation	[1]

14 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 NEDD4 family-interacting protein 2 (NDFIP2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[9]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[11]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of NEDD4 family-interacting protein 2 (NDFIP2).	[15]

References

• [1] Genetic variations in the sodium balance-regulating genes ENaC, NEDD4L, NDFIP2 and USP2 influence blood pressure and hypertension.Kidney Blood Press Res. 2010;33(1):15-23. doi: 10.1159/000275706. Epub 2010 Jan 15.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] 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.
• [8] 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.
• [9] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [10] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [14] 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.
• [15] 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.