Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHPD5LB)

• DOT Name: PDZ domain-containing RING finger protein 4 (PDZRN4)
• Synonyms: Ligand of Numb protein X 4; SEMACAP3-like protein
• Gene Name: PDZRN4
• Related Disease:
  Multiple sclerosis
  Hepatocellular carcinoma
  Motion sickness
  Neoplasm
  Asthma
• UniProt ID: PZRN4_HUMAN
• Pfam ID: PF00595 ; PF13923
• Sequence:
  MGFALERFAEAVDPALECKLCGQVLEEPLCTPCGHVFCASCLLPWAVRRRRCPLQCQPLA
  PGELYRVLPLRSLIQKLRVQCDYRARGCGHSVRLHELEAHVEHCDFGPARRLRSRGGCAS
  GLGGGEVPARGGCGPTPRAGRGGGARGGPPGGRWGRGRGPGPRVLAWRRREKALLAQLWA
  LQGEVQLTARRYQEKFTQYMAHVRNFVGDLGGGHRRDGEHKPFTIVLERENDTLGFNIIG
  GRPNQNNQEGTSTEGIYVSKILENGPADRADGLEIHDKIMEVNGKDLSKATHEEAVEAFR
  NAKEPIVVQVLRRTPLSRPAYGMASEVQLMNASTQTDITFEHIMALAKLRPPTPPVPDIC
  PFLLSDSCHSLHPMEHEFYEDNEYISSLPADADRTEDFEYEEVELCRVSSQEKLGLTVCY
  RTDDEEDTGIYVSEVDPNSIAAKDGRIREGDRILQINGEDVQNREEAVALLSNDECKRIV
  LLVARPEIQLDEGWLEDERNEFLEELNLEMLEEEHNEAMQPTANEVEQPKKQEEEEGTTD
  TATSSSNNHEKDSGVGRTDESLRNDESSEQENAAEDPNSTSLKSKRDLGQSQDTLGSVEL
  QYNESLVSGEYIDSDCIGNPDEDCERFRQLLELKCKIRNHGEYDLYYSSSTIECNQGEQE
  GVEHELQLLNEELRNIELECQNIMQAHRLQKVTDQYGDIWTLHDGGFRNYNTSIDMQRGK
  LDDIMEHPEKSDKDSSSAYNTAESCRSTPLTVDRSPDSSLPRVINLTNKKNLRSTMAATQ
  SSSGQSSKESTSTKAKTTEQGCSAESKEKVLEGSKLPDQEKAVSEHIPYLSPYHSSSYRY
  ANIPAHARHYQSYMQLIQQKSAVEYAQSQLSLVSMCKESQKCSEPKMEWKVKIRSDGTRY
  ITKRPVRDRILKERALKIKEERSGMTTDDDTMSEMKMGRYWSKEERKQHLVRAKEQRRRR
  EFMMRSRLECLKESPQSGSEGKKEINIIELSHKKMMKKRNKKILDNWMTIQELMTHGAKS
  PDGTRVHNAFLSVTTV

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Motion sickness	DISZ2WZW	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Asthma	DISW9QNS	moderate	Genetic Variation	[4]

3 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 PDZ domain-containing RING finger protein 4 (PDZRN4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PDZ domain-containing RING finger protein 4 (PDZRN4).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of PDZ domain-containing RING finger protein 4 (PDZRN4).	[7]

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 increases the methylation of PDZ domain-containing RING finger protein 4 (PDZRN4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of PDZ domain-containing RING finger protein 4 (PDZRN4).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of PDZ domain-containing RING finger protein 4 (PDZRN4).	[10]

References

• [1] Replication of top markers of a genome-wide association study in multiple sclerosis in Spain.Genes Immun. 2011 Mar;12(2):110-5. doi: 10.1038/gene.2010.52. Epub 2010 Oct 14.
• [2] PDZRN4 acts as a suppressor of cell proliferation in human liver cancer cell lines.Cell Biochem Funct. 2015 Oct;33(7):443-9. doi: 10.1002/cbf.3130. Epub 2015 Oct 20.
• [3] Genetic variants associated with motion sickness point to roles for inner ear development, neurological processes and glucose homeostasis.Hum Mol Genet. 2015 May 1;24(9):2700-8. doi: 10.1093/hmg/ddv028. Epub 2015 Jan 26.
• [4] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] 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.
• [7] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [8] 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.
• [9] 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.
• [10] 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.