Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA6GA4F)

• DOT Name: Atypical chemokine receptor 3 (ACKR3)
• Synonyms: C-X-C chemokine receptor type 7; CXC-R7; CXCR-7; Chemokine orphan receptor 1; G-protein coupled receptor 159; G-protein coupled receptor RDC1 homolog; RDC-1
• Gene Name: ACKR3
• Related Disease: Oculomotor-abducens synkinesis
• UniProt ID: ACKR3_HUMAN
• PDB ID: 6K3F; 7SK3; 7SK4; 7SK5; 7SK6; 7SK7; 7SK8; 7SK9
• Pfam ID: PF00001
• Sequence:
  MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMI
  ANSVVVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVT
  HLIFSINLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVWLLAFCVSLPDT
  YYLKTVTSASNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAIS
  ASSDQEKHSSRKIIFSYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVT
  QCLSLVHCCVNPVLYSFINRNYRYELMKAFIFKYSAKTGLTKLIDASRVSETEYSALEQS
  TK
• Function: Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines CXCL11 and CXCL12/SDF1. Chemokine binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization and activation of MAPK signaling pathway. Required for regulation of CXCR4 protein levels in migrating interneurons, thereby adapting their chemokine responsiveness. In glioma cells, transduces signals via MEK/ERK pathway, mediating resistance to apoptosis. Promotes cell growth and survival. Not involved in cell migration, adhesion or proliferation of normal hematopoietic progenitors but activated by CXCL11 in malignant hemapoietic cells, leading to phosphorylation of ERK1/2 (MAPK3/MAPK1) and enhanced cell adhesion and migration. Plays a regulatory role in CXCR4-mediated activation of cell surface integrins by CXCL12. Required for heart valve development. Regulates axon guidance in the oculomotor system through the regulation of CXCL12 levels ; (Microbial infection) Acts as a coreceptor with CXCR4 for a restricted number of HIV isolates.
• Tissue Specificity: Expressed in monocytes, basophils, B-cells, umbilical vein endothelial cells (HUVEC) and B-lymphoblastoid cells. Lower expression detected in CD4+ T-lymphocytes and natural killer cells. In the brain, detected in endothelial cells and capillaries, and in mature neurons of the frontal cortex and hippocampus. Expressed in tubular formation in the kidney. Highly expressed in astroglial tumor endothelial, microglial and glioma cells. Expressed at low levels in normal CD34+ progenitor cells, but at very high levels in several myeloid malignant cell lines. Expressed in breast carcinomas but not in normal breast tissue (at protein level).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Oculomotor-abducens synkinesis	DISILVN9	Limited	Unknown	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Atypical chemokine receptor 3 (ACKR3) decreases the response to substance of Paclitaxel.	[27]

30 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 Atypical chemokine receptor 3 (ACKR3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Atypical chemokine receptor 3 (ACKR3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Atypical chemokine receptor 3 (ACKR3).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Atypical chemokine receptor 3 (ACKR3).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Atypical chemokine receptor 3 (ACKR3).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Atypical chemokine receptor 3 (ACKR3).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Atypical chemokine receptor 3 (ACKR3).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Atypical chemokine receptor 3 (ACKR3).	[16]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Atypical chemokine receptor 3 (ACKR3).	[18]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Atypical chemokine receptor 3 (ACKR3).	[19]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[14]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[20]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Atypical chemokine receptor 3 (ACKR3).	[21]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[22]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[14]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Atypical chemokine receptor 3 (ACKR3).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Atypical chemokine receptor 3 (ACKR3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Atypical chemokine receptor 3 (ACKR3).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Atypical chemokine receptor 3 (ACKR3).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Atypical chemokine receptor 3 (ACKR3).	[19]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Atypical chemokine receptor 3 (ACKR3).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Atypical chemokine receptor 3 (ACKR3).	[8]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Atypical chemokine receptor 3 (ACKR3).	[17]

References

• [1] Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans. Hum Mol Genet. 2019 Sep 15;28(18):3113-3125. doi: 10.1093/hmg/ddz137.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [8] Changes in DNA methylation in APOE and ACKR3 genes in multiple sclerosis patients and the relationship with their heavy metal blood levels. Neurotoxicology. 2021 Dec;87:182-187. doi: 10.1016/j.neuro.2021.09.008. Epub 2021 Oct 6.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] 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.
• [14] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] 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.
• [18] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [21] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [22] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [23] Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. Mol Cell Biochem. 2011 Nov;357(1-2):83-94. doi: 10.1007/s11010-011-0878-2. Epub 2011 May 19.
• [24] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [26] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [27] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.