Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWYY14H)

DOT Name	Atypical chemokine receptor 2 (ACKR2)
Synonyms	C-C chemokine receptor D6; Chemokine receptor CCR-10; Chemokine receptor CCR-9; Chemokine-binding protein 2; Chemokine-binding protein D6
Gene Name	ACKR2
Related Disease	Arthritis ( ) Arthropathy ( ) Melanoma ( ) Advanced cancer ( ) Alzheimer disease ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Chronic kidney disease ( ) Chronic renal failure ( ) Dermatitis ( ) Multiple sclerosis ( ) Neoplasm ( ) Nephritis ( ) Psoriasis ( ) Pulmonary fibrosis ( ) Renal fibrosis ( ) Renal tubule disorder ( ) Crohn disease ( ) Glomerulonephritis ( ) Coronary atherosclerosis ( ) Coronary heart disease ( ) Diabetic kidney disease ( ) Nervous system inflammation ( ) Obesity ( ) Squamous cell carcinoma ( ) Type-1/2 diabetes ( )
UniProt ID	ACKR2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00001
Sequence	MAATASPQPLATEDADSENSSFYYYDYLDEVAFMLCRKDAVVSFGKVFLPVFYSLIFVLG LSGNLLLLMVLLRYVPRRRMVEIYLLNLAISNLLFLVTLPFWGISVAWHWVFGSFLCKMV STLYTINFYSGIFFISCMSLDKYLEIVHAQPYHRLRTRAKSLLLATIVWAVSLAVSIPDM VFVQTHENPKGVWNCHADFGGHGTIWKLFLRFQQNLLGFLLPLLAMIFFYSRIGCVLVRL RPAGQGRALKIAAALVVAFFVLWFPYNLTLFLHTLLDLQVFGNCEVSQHLDYALQVTESI AFLHCCFSPILYAFSSHRFRQYLKAFLAAVLGWHLAPGTAQASLSSCSESSILTAQEEMT GMNDLGERQSENYPNKEDVGNKSA
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 including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. By scavenging chemokines in tissues, on the surfaces of lymphatic vessels, and in placenta, plays an essential role in the resolution (termination) of the inflammatory response and in the regulation of adaptive immune responses. Plays a major role in the immune silencing of macrophages during the resolution of inflammation. Acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells (LECs) and is required for immature/mature dendritic cells discrimination by LECs.
Tissue Specificity	Found in endothelial cells lining afferent lymphatics in dermis and lymph nodes. Also found in lymph nodes subcapsular and medullary sinuses, tonsillar lymphatic sinuses and lymphatics in mucosa and submucosa of small and large intestine and appendix. Also found in some malignant vascular tumors. Expressed at high levels in Kaposi sarcoma-related pathologies. Expressed on apoptotic neutrophils (at protein level). Expressed primarily in placenta and fetal liver, and found at very low levels in the lung and lymph node.
Reactome Pathway	Chemokine receptors bind chemokines (R-HSA-380108 )

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Arthritis	DIST1YEL	Definitive	Altered Expression	[1]
Arthropathy	DISVEERK	Definitive	Altered Expression	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[7]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[7]
Dermatitis	DISY5SZC	Strong	Biomarker	[8]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Nephritis	DISQZQ70	Strong	Altered Expression	[11]
Psoriasis	DIS59VMN	Strong	Biomarker	[12]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[13]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[7]
Renal tubule disorder	DISAFXMQ	Strong	Biomarker	[7]
Crohn disease	DIS2C5Q8	Disputed	Altered Expression	[14]
Glomerulonephritis	DISPZIQ3	Disputed	Biomarker	[15]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[16]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[16]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[17]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[18]
Obesity	DIS47Y1K	Limited	Altered Expression	[19]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[10]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[17]
------------------------------------------------------------------------------------


⏷ Show the Full List of 27 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Atypical chemokine receptor 2 (ACKR2).	[20]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Atypical chemokine receptor 2 (ACKR2).	[22]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Atypical chemokine receptor 2 (ACKR2).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Atypical chemokine receptor 2 (ACKR2).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Atypical chemokine receptor 2 (ACKR2).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Atypical chemokine receptor 2 (ACKR2).	[26]
------------------------------------------------------------------------------------


⏷ Show the Full List of 6 Drug(s)

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Atypical chemokine receptor 2 (ACKR2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Atypical chemokine receptor 2 (ACKR2).	[25]
------------------------------------------------------------------------------------

References

1	Elevated ACKR2 expression is a common feature of inflammatory arthropathies.Rheumatology (Oxford). 2017 Sep 1;56(9):1607-1617. doi: 10.1093/rheumatology/kex176.
2	ACKR2 in hematopoietic precursors as a checkpoint of neutrophil release and anti-metastatic activity.Nat Commun. 2018 Feb 14;9(1):676. doi: 10.1038/s41467-018-03080-8.
3	ACKR2: An Atypical Chemokine Receptor Regulating Lymphatic Biology.Front Immunol. 2017 Jan 11;7:691. doi: 10.3389/fimmu.2016.00691. eCollection 2016.
4	Genome-wide association study of CSF levels of 59 alzheimer's disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation.PLoS Genet. 2014 Oct 23;10(10):e1004758. doi: 10.1371/journal.pgen.1004758. eCollection 2014 Oct.
5	A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer.Clin Cancer Res. 2019 Jun 15;25(12):3702-3717. doi: 10.1158/1078-0432.CCR-18-1294. Epub 2019 Mar 8.
6	Chemokine decoy receptor d6 plays a negative role in human breast cancer.Mol Cancer Res. 2008 Aug;6(8):1276-88. doi: 10.1158/1541-7786.MCR-07-2108.
7	The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury.Am J Pathol. 2019 Feb;189(2):231-247. doi: 10.1016/j.ajpath.2018.09.016. Epub 2018 Nov 16.
8	Spread of Psoriasiform Inflammation to Remote Tissues Is Restricted by the Atypical Chemokine Receptor ACKR2.J Invest Dermatol. 2017 Jan;137(1):85-94. doi: 10.1016/j.jid.2016.07.039. Epub 2016 Aug 26.
9	A critical role for expression of atypical chemokine receptor 2 in multiple sclerosis: A preliminary project.Mult Scler Relat Disord. 2020 Feb;38:101524. doi: 10.1016/j.msard.2019.101524. Epub 2019 Nov 14.
10	Role of atypical chemokine receptor ACKR2 in experimental oral squamous cell carcinogenesis.Cytokine. 2019 Jun;118:160-167. doi: 10.1016/j.cyto.2018.03.001. Epub 2018 Mar 15.
11	The atypical chemokine receptor 2 limits renal inflammation and fibrosis in murine progressive immune complex glomerulonephritis.Kidney Int. 2018 Apr;93(4):826-841. doi: 10.1016/j.kint.2017.11.013. Epub 2018 Feb 1.
12	MicroRNA-146 and cell trauma down-regulate expression of the psoriasis-associated atypical chemokine receptor ACKR2.J Biol Chem. 2018 Feb 23;293(8):3003-3012. doi: 10.1074/jbc.M117.809780. Epub 2017 Dec 26.
13	The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2(+) and CCR5(+) IFN-producing T cells in mice.Am J Physiol Lung Cell Mol Physiol. 2018 Jun 1;314(6):L1010-L1025. doi: 10.1152/ajplung.00233.2017. Epub 2018 Feb 22.
14	The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4.J Immunol. 2007 Sep 1;179(5):3109-18. doi: 10.4049/jimmunol.179.5.3109.
15	Atypical chemokine receptors-"chemokine PACMANs" as new therapeutic targets in glomerulonephritis.Kidney Int. 2018 Apr;93(4):774-775. doi: 10.1016/j.kint.2017.12.021.
16	Genetic variation associated with circulating monocyte count in the eMERGE Network.Hum Mol Genet. 2013 May 15;22(10):2119-27. doi: 10.1093/hmg/ddt010. Epub 2013 Jan 12.
17	Renal Protection by Genetic Deletion of the Atypical Chemokine Receptor ACKR2 in Diabetic OVE Mice.J Diabetes Res. 2016;2016:5362506. doi: 10.1155/2016/5362506. Epub 2015 Dec 20.
18	Role of Atypical Chemokine Receptors in Microglial Activation and Polarization.Front Aging Neurosci. 2017 May 26;9:148. doi: 10.3389/fnagi.2017.00148. eCollection 2017.
19	Hypothalamic expression of the atypical chemokine receptor ACKR2 is involved in the systemic regulation of glucose tolerance.Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1126-1137. doi: 10.1016/j.bbadis.2019.01.001. Epub 2019 Feb 7.
20	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
21	Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
22	Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
23	Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
24	Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
25	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.
26	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.