Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN1DQOY)

• DOT Name: E3 ubiquitin-protein ligase NRDP1 (RNF41)
• Synonyms: EC 2.3.2.27; RING finger protein 41; RING-type E3 ubiquitin transferase NRDP1
• Gene Name: RNF41
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Autosomal recessive juvenile Parkinson disease 2
  Bipolar disorder
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Castration-resistant prostate carcinoma
  Glioma
  Lentivirus infection
  Major depressive disorder
  Mental disorder
  Neoplasm
  Osteoglophonic dwarfism
  Pheochromocytoma
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Obesity
  Small lymphocytic lymphoma
  Colorectal carcinoma
  Congenital heart disease
• UniProt ID: RNF41_HUMAN
• PDB ID: 2FZP; 2GWF
• EC Number: 2.3.2.27
• Pfam ID: PF08941 ; PF13923
• Sequence:
  MGYDVTRFQGDVDEDLICPICSGVLEEPVQAPHCEHAFCNACITQWFSQQQTCPVDRSVV
  TVAHLRPVPRIMRNMLSKLQIACDNAVFGCSAVVRLDNLMSHLSDCEHNPKRPVTCEQGC
  GLEMPKDELPNHNCIKHLRSVVQQQQTRIAELEKTSAEHKHQLAEQKRDIQLLKAYMRAI
  RSVNPNLQNLEETIEYNEILEWVNSLQPARVTRWGGMISTPDAVLQAVIKRSLVESGCPA
  SIVNELIENAHERSWPQGLATLETRQMNRRYYENYVAKRIPGKQAVVVMACENQHMGDDM
  VQEPGLVMIFAHGVEEI
• Function: Acts as E3 ubiquitin-protein ligase and regulates the degradation of target proteins. Polyubiquitinates MYD88. Negatively regulates MYD88-dependent production of pro-inflammatory cytokines. Can promote TRIF-dependent production of type I interferon and inhibits infection with vesicular stomatitis virus. Promotes also activation of TBK1 and IRF3. Involved in the ubiquitination of erythropoietin (EPO) and interleukin-3 (IL-3) receptors. Thus, through maintaining basal levels of cytokine receptors, RNF41 is involved in the control of hematopoietic progenitor cell differentiation into myeloerythroid lineages. Contributes to the maintenance of steady-state ERBB3 levels by mediating its growth factor-independent degradation. Involved in the degradation of the inhibitor of apoptosis BIRC6 and thus is an important regulator of cell death by promoting apoptosis. Acts also as a PRKN modifier that accelerates its degradation, resulting in a reduction of PRKN activity, influencing the balance of intracellular redox state. The RNF41-PRKN pathway regulates autophagosome-lysosome fusion during late mitophagy. Mitophagy is a selective form of autophagy necessary for mitochondrial quality control.
• Tissue Specificity: Detected in ovary, testis and prostate.
• KEGG Pathway: Endocytosis (hsa04144)
• Reactome Pathway:
  Antigen processing (R-HSA-983168)
  Downregulation of ERBB2 (R-HSA-1358803)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[1]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[7]
Lentivirus infection	DISX17PY	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[3]
Mental disorder	DIS3J5R8	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Osteoglophonic dwarfism	DISVSNPT	Strong	Altered Expression	[10]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[10]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[11]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[9]
Obesity	DIS47Y1K	moderate	Biomarker	[12]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[13]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[14]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase NRDP1 (RNF41).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase NRDP1 (RNF41).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase NRDP1 (RNF41).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase NRDP1 (RNF41).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of E3 ubiquitin-protein ligase NRDP1 (RNF41).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase NRDP1 (RNF41).	[21]

References

• [1] Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer.Endocr Relat Cancer. 2015 Jun;22(3):369-86. doi: 10.1530/ERC-15-0021. Epub 2015 Mar 10.
• [2] Suppression of Nrdp1 toxicity by Parkin in Drosophila models.Biochem Biophys Res Commun. 2011 Dec 9;416(1-2):18-23. doi: 10.1016/j.bbrc.2011.10.104. Epub 2011 Nov 6.
• [3] An E3 ubiquitin ligase, Really Interesting New Gene (RING) Finger 41, is a candidate gene for anxiety-like behavior and beta-carboline-induced seizures.Biol Psychiatry. 2009 Mar 1;65(5):425-31. doi: 10.1016/j.biopsych.2008.09.015. Epub 2008 Nov 4.
• [4] Clinicopathological and prognostic correlations of HER3 expression and its degradation regulators, NEDD4-1 and NRDP1, in primary breast cancer.BMC Cancer. 2018 Oct 26;18(1):1045. doi: 10.1186/s12885-018-4917-1.
• [5] Oligomerization of the Nrdp1 E3 ubiquitin ligase is necessary for efficient autoubiquitination but not ErbB3 ubiquitination.J Biol Chem. 2014 Mar 21;289(12):8570-8. doi: 10.1074/jbc.M113.527036. Epub 2014 Feb 11.
• [6] The ErbB family and androgen receptor signaling are targets ofCelecoxib in prostate cancer.Cancer Lett. 2017 Aug 1;400:9-17. doi: 10.1016/j.canlet.2017.04.025. Epub 2017 Apr 25.
• [7] Nrdp1-mediated ErbB3 degradation inhibits glioma cell migration and invasion by reducing cytoplasmic localization of p27(Kip1).J Neurooncol. 2015 Sep;124(3):357-64. doi: 10.1007/s11060-015-1851-9. Epub 2015 Jun 19.
• [8] Nrdp1 is involved in hippocampus apoptosis in cardiopulmonary bypass-induced cognitive dysfunction via the regulation of ErbB3 protein levels.Int J Mol Med. 2019 Apr;43(4):1747-1757. doi: 10.3892/ijmm.2019.4080. Epub 2019 Jan 28.
• [9] CACYBP Enhances Cytoplasmic Retention of P27(Kip1) to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation.Theranostics. 2019 Oct 22;9(26):8392-8408. doi: 10.7150/thno.36838. eCollection 2019.
• [10] Nrdp1 Increases Ischemia Induced Primary Rat Cerebral Cortical Neurons and Pheochromocytoma Cells Apoptosis Via Downregulation of HIF-1 Protein.Front Cell Neurosci. 2017 Sep 20;11:293. doi: 10.3389/fncel.2017.00293. eCollection 2017.
• [11] Suppression of planar cell polarity signaling and migration in glioblastoma by Nrdp1-mediated Dvl polyubiquitination.Oncogene. 2017 Sep 7;36(36):5158-5167. doi: 10.1038/onc.2017.126. Epub 2017 May 8.
• [12] Decreased RNF41 expression leads to insulin resistance in skeletal muscle of obese women.Metabolism. 2018 Jun;83:81-91. doi: 10.1016/j.metabol.2018.01.014. Epub 2018 Feb 2.
• [13] Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL).PLoS One. 2009 Sep 25;4(9):e7169. doi: 10.1371/journal.pone.0007169.
• [14] KITENIN functions as a fine regulator of ErbB4 expression level in colorectal cancer via protection of ErbB4 from E3-ligase Nrdp1-mediated degradation.Mol Carcinog. 2017 Mar;56(3):1068-1081. doi: 10.1002/mc.22572. Epub 2016 Oct 26.
• [15] Association between RNF41 gene c.-206 T > A genetic polymorphism and risk of congenital heart diseases in the Chinese Mongolian population.Genet Mol Res. 2016 Jun 17;15(2). doi: 10.4238/gmr.15028089.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.