Details of Drug Off-Target (DOT)

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

• DOT Name: NEDD4 family-interacting protein 1 (NDFIP1)
• Synonyms: Breast cancer-associated protein SGA-1M; NEDD4 WW domain-binding protein 5; Putative MAPK-activating protein PM13; Putative NF-kappa-B-activating protein 164; Putative NFKB and MAPK-activating protein
• Gene Name: NDFIP1
• Related Disease:
  Hepatocellular carcinoma
  Stroke
  Alzheimer disease
  Colitis
  Influenza
  Multiple sclerosis
  Parkinson disease
  Asthma
  Ankylosing spondylitis
  Crohn disease
  Inflammatory bowel disease
  Psoriasis
  Sclerosing cholangitis
  Ulcerative colitis
• UniProt ID: NFIP1_HUMAN
• Pfam ID: PF10176
• Sequence:
  MALALAALAAVEPACGSRYQQLQNEEESGEPEQAAGDAPPPYSSISAESAAYFDYKDESG
  FPKPPSYNVATTLPSYDEAERTKAEATIPLVPGRDEDFVGRDDFDDADQLRIGNDGIFML
  TFFMAFLFNWIGFFLSFCLTTSAAGRYGAISGFGLSLIKWILIVRFSTYFPGYFDGQYWL
  WWVFLVLGFLLFLRGFINYAKVRKMPETFSNLPRTRVLFIY
• Function: Activates HECT domain-containing E3 ubiquitin-protein ligases, including NEDD4 and ITCH, and consequently modulates the stability of their targets. As a result, controls many cellular processes. Prevents chronic T-helper cell-mediated inflammation by activating ITCH and thus controlling JUNB degradation. Promotes pancreatic beta cell death through degradation of JUNB and inhibition of the unfolded protein response, leading to reduction of insulin secretion. Restricts the production of pro-inflammatory cytokines in effector Th17 T-cells by promoting ITCH-mediated ubiquitination and degradation of RORC. Together with NDFIP2, limits the cytokine signaling and expansion of effector Th2 T-cells by promoting degradation of JAK1, probably by ITCH- and NEDD4L-mediated ubiquitination. Regulates peripheral T-cell tolerance to self and foreign antigens, forcing the exit of naive CD4+ T-cells from the cell cycle before they become effector T-cells. Negatively regulates RLR-mediated antiviral response by promoting SMURF1-mediated ubiquitination and subsequent degradation of MAVS. 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 where it mediates KCNH2 degradation. In cortical neurons, mediates the ubiquitination of the divalent metal transporter SLC11A2/DMT1 by NEDD4L, leading to its down-regulation and protection of the cells from cobalt and iron toxicity. Important for normal development of dendrites and dendritic spines in cortex. Enhances the ubiquitination of BRAT1 mediated by: NEDD4, NEDD4L and ITCH and is required for the nuclear localization of ubiquitinated BRAT1. Enhances the ITCH-mediated ubiquitination of MAP3K7 by recruiting E2 ubiquitin-conjugating enzyme UBE2L3 to ITCH. Modulates EGFR signaling through multiple pathways. In particular, may regulate the ratio of AKT1-to-MAPK8 signaling in response to EGF, acting on AKT1 probably through PTEN destabilization and on MAPK8 through ITCH-dependent MAP2K4 inactivation. As a result, may control cell growth rate. Inhibits cell proliferation by promoting PTEN nuclear localization and changing its signaling specificity.
• Tissue Specificity: Widely expressed. Higher levels are detected in cerebellum, pituitary, thalamus, kidney, liver, testis, salivary glands and placenta. Also expressed in fetal brain, kidney and lung.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Stroke	DISX6UHX	Definitive	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Colitis	DISAF7DD	Strong	Biomarker	[4]
Influenza	DIS3PNU3	Strong	Biomarker	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[7]
Asthma	DISW9QNS	moderate	Genetic Variation	[8]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[9]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[10]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[10]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[9]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[9]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[16]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of NEDD4 family-interacting protein 1 (NDFIP1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of NEDD4 family-interacting protein 1 (NDFIP1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of NEDD4 family-interacting protein 1 (NDFIP1).	[17]

References

• [1] The miR-873/NDFIP1 axis promotes hepatocellular carcinoma growth and metastasis through the AKT/mTOR-mediated Warburg effect.Am J Cancer Res. 2019 May 1;9(5):927-944. eCollection 2019.
• [2] Differential regulation of Nedd4 ubiquitin ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke.Exp Neurol. 2012 May;235(1):326-35. doi: 10.1016/j.expneurol.2012.02.014. Epub 2012 Mar 5.
• [3] Lower Expression of Ndfip1 Is Associated With Alzheimer Disease Pathogenesis Through Decreasing DMT1 Degradation and Increasing Iron Influx.Front Aging Neurosci. 2018 Jun 8;10:165. doi: 10.3389/fnagi.2018.00165. eCollection 2018.
• [4] Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production.Sci Rep. 2017 Jan 4;7:39649. doi: 10.1038/srep39649.
• [5] Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7.J Immunol. 2015 Mar 1;194(5):2160-7. doi: 10.4049/jimmunol.1402742. Epub 2015 Jan 28.
• [6] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [7] Ndfip1 attenuated 6-OHDA-induced iron accumulation via regulating the degradation of DMT1.Neurobiol Aging. 2015 Feb;36(2):1183-93. doi: 10.1016/j.neurobiolaging.2014.10.021. Epub 2014 Oct 18.
• [8] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [9] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [10] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.