Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC2R00C)

• DOT Name: Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2)
• Synonyms: Syndapin-2; Syndapin-II; SdpII
• Gene Name: PACSIN2
• Related Disease:
  Cardiovascular disease
  Diabetic kidney disease
  Hepatitis C virus infection
  Inflammatory bowel disease
  Juvenile idiopathic arthritis
  leukaemia
  Leukemia
  Acute lymphocytic leukaemia
  Childhood acute lymphoblastic leukemia
• UniProt ID: PACN2_HUMAN
• PDB ID: 3ABH; 3ACO; 3HAJ; 3Q0K
• Pfam ID: PF00611 ; PF14604
• Sequence:
  MSVTYDDSVGVEVSSDSFWEVGNYKRTVKRIDDGHRLCSDLMNCLHERARIEKAYAQQLT
  EWARRWRQLVEKGPQYGTVEKAWMAFMSEAERVSELHLEVKASLMNDDFEKIKNWQKEAF
  HKQMMGGFKETKEAEDGFRKAQKPWAKKLKEVEAAKKAHHAACKEEKLAISREANSKADP
  SLNPEQLKKLQDKIEKCKQDVLKTKEKYEKSLKELDQGTPQYMENMEQVFEQCQQFEEKR
  LRFFREVLLEVQKHLDLSNVAGYKAIYHDLEQSIRAADAVEDLRWFRANHGPGMAMNWPQ
  FEEWSADLNRTLSRREKKKATDGVTLTGINQTGDQSLPSKPSSTLNVPSNPAQSAQSQSS
  YNPFEDEDDTGSTVSEKDDTKAKNVSSYEKTQSYPTDWSDDESNNPFSSTDANGDSNPFD
  DDATSGTEVRVRALYDYEGQEHDELSFKAGDELTKMEDEDEQGWCKGRLDNGQVGLYPAN
  YVEAIQ
• Function: Regulates the morphogenesis and endocytosis of caveolae. Lipid-binding protein that is able to promote the tubulation of the phosphatidic acid-containing membranes it preferentially binds. Plays a role in intracellular vesicle-mediated transport. Involved in the endocytosis of cell-surface receptors like the EGF receptor, contributing to its internalization in the absence of EGF stimulus; (Microbial infection) Specifically enhances the efficiency of HIV-1 virion spread by cell-to-cell transfer. Also promotes the protrusion engulfment during cell-to-cell spread of bacterial pathogens like Listeria monocytogenes. Involved in lipid droplet formation, which is important for HCV virion assembly.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: Clathrin-mediated endocytosis (R-HSA-8856828)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[3]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[4]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[5]
leukaemia	DISS7D1V	Strong	Genetic Variation	[6]
Leukemia	DISNAKFL	Strong	Genetic Variation	[6]
Acute lymphocytic leukaemia	DISPX75S	Limited	Genetic Variation	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[10]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein kinase C and casein kinase substrate in neurons protein 2 (PACSIN2).	[16]

References

• [1] Pacsin 2 is required for the maintenance of a normal cardiac function in the developing mouse heart.Pharmacol Res. 2018 Feb;128:200-210. doi: 10.1016/j.phrs.2017.10.004. Epub 2017 Oct 28.
• [2] PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease.FASEB J. 2017 Sep;31(9):3978-3990. doi: 10.1096/fj.201601265R. Epub 2017 May 26.
• [3] PACSIN2 Interacts with Nonstructural Protein 5A and Regulates Hepatitis C Virus Assembly.J Virol. 2020 Feb 14;94(5):e01531-19. doi: 10.1128/JVI.01531-19. Print 2020 Feb 14.
• [4] PACSIN2 rs2413739 influence on thiopurine pharmacokinetics: validation studies in pediatric patients.Pharmacogenomics J. 2020 Jun;20(3):415-425. doi: 10.1038/s41397-019-0130-0. Epub 2019 Dec 3.
• [5] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [6] PACSIN2 polymorphism influences TPMT activity and mercaptopurine-related gastrointestinal toxicity. Hum Mol Genet. 2012 Nov 1;21(21):4793-804.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] 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.
• [10] 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.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] 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.
• [16] 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.
• [17] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.