Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPU9HUA)

• DOT Name: Phosphofurin acidic cluster sorting protein 2 (PACS2)
• Synonyms: PACS-2; PACS1-like protein
• Gene Name: PACS2
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Colitis
  Colorectal carcinoma
  Developmental and epileptic encephalopathy, 66
  Epilepsy
  Intellectual disability
  Neoplasm
• UniProt ID: PACS2_HUMAN
• Pfam ID: PF10254
• Sequence:
  MAERGRLGLPGAPGALNTPVPMNLFATWEVDGSSPSCVPRLCSLTLKKLVVFKELEKELI
  SVVIAVKMQGSKRILRSHEIVLPPSGQVETDLALTFSLQYPHFLKREGNKLQIMLQRRKR
  YKNRTILGYKTLAAGSISMAEVMQHPSEGGQVLSLCSSIKEAPVKAAEIWIASLSSQPID
  HEDSTMQAGPKAKSTDNYSEEEYESFSSEQEASDDAVQGQDLDEDDFDVGKPKKQRRSIV
  RTTSMTRQQNFKQKVVALLRRFKVSDEVLDSEQDPAEHIPEAEEDLDLLYDTLDMEHPSD
  SGPDMEDDDSVLSTPKPKLRPYFEGLSHSSSQTEIGSIHSARSHKEPPSPADVPEKTRSL
  GGRQPSDSVSDTVALGVPGPREHPGQPEDSPEAEASTLDVFTERLPPSGRITKTESLVIP
  STRSEGKQAGRRGRSTSLKERQAARPQNERANSLDNERCPDARSQLQIPRKTVYDQLNHI
  LISDDQLPENIILVNTSDWQGQFLSDVLQRHTLPVVCTCSPADVQAAFSTIVSRIQRYCN
  CNSQPPTPVKIAVAGAQHYLSAILRLFVEQLSHKTPDWLGYMRFLVIPLGSHPVARYLGS
  VDYRYNNFFQDLAWRDLFNKLEAQSAVQDTPDIVSRITQYIAGANCAHQLPIAEAMLTYK
  QKSPDEESSQKFIPFVGVVKVGIVEPSSATSGDSDDAAPSGSGTLSSTPPSASPAAKEAS
  PTPPSSPSVSGGLSSPSQGVGAELMGLQVDYWTAAQPADRKRDAEKKDLPVTKNTLKCTF
  RSLQVSRLPSSGEAAATPTMSMTVVTKEKNKKVMFLPKKAKDKDVESKSQCIEGISRLIC
  TARQQQNMLRVLIDGVECSDVKFFQLAAQWSSHVKHFPICIFGHSKATF
• Function: Multifunctional sorting protein that controls the endoplasmic reticulum (ER)-mitochondria communication, including the apposition of mitochondria with the ER and ER homeostasis. In addition, in response to apoptotic inducer, translocates BIB to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated BID, the release of cytochrome c, the activation of caspase-3 thereby causing cell death. May also be involved in ion channel trafficking, directing acidic cluster-containing ion channels to distinct subcellular compartments.
• Tissue Specificity: Broadly expressed, with greatest levels in skeletal muscle followed by heart, brain, pancreas and testis.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[1]
Colitis	DISAF7DD	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Developmental and epileptic encephalopathy, 66	DIS6OQ8P	Strong	Autosomal dominant	[3]
Epilepsy	DISBB28L	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]

5 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 Phosphofurin acidic cluster sorting protein 2 (PACS2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphofurin acidic cluster sorting protein 2 (PACS2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphofurin acidic cluster sorting protein 2 (PACS2).	[8]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Phosphofurin acidic cluster sorting protein 2 (PACS2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphofurin acidic cluster sorting protein 2 (PACS2).	[11]

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 Phosphofurin acidic cluster sorting protein 2 (PACS2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phosphofurin acidic cluster sorting protein 2 (PACS2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphofurin acidic cluster sorting protein 2 (PACS2).	[13]

References

• [1] PACS2 is required for ox-LDL-induced endothelial cell apoptosis by regulating mitochondria-associated ER membrane formation and mitochondrial Ca(2+) elevation.Exp Cell Res. 2019 Jun 15;379(2):191-202. doi: 10.1016/j.yexcr.2019.04.002. Epub 2019 Apr 7.
• [2] Loss of PACS-2 delays regeneration in DSS-induced colitis but does not affect the Apc(Min) model of colorectal cancer.Oncotarget. 2017 Nov 26;8(65):108303-108315. doi: 10.18632/oncotarget.22661. eCollection 2017 Dec 12.
• [3] Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Nat Neurosci. 2017 Aug;20(8):1043-1051. doi: 10.1038/nn.4589. Epub 2017 Jun 19.
• [4] A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.Am J Hum Genet. 2018 May 3;102(5):995-1007. doi: 10.1016/j.ajhg.2018.03.005. Epub 2018 Apr 12.
• [5] Expanding the clinical spectrum associated with PACS2 mutations.Clin Genet. 2019 Apr;95(4):525-531. doi: 10.1111/cge.13516. Epub 2019 Feb 28.
• [6] 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.
• [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] 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.
• [9] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.