Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5PX0RX)

• DOT Name: C-C chemokine receptor-like 2 (CCRL2)
• Synonyms: Chemokine receptor CCR11; Chemokine receptor X; Putative MCP-1 chemokine receptor
• Gene Name: CCRL2
• Related Disease:
  Arthritis
  Breast cancer
  Breast carcinoma
  Crohn disease
  Alzheimer disease
  Carcinoma of esophagus
  Cardiovascular disease
  Factor IX deficiency
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Psoriasis
  Psoriatic arthritis
  Skin ulcer
  Adult glioblastoma
  Cutaneous squamous cell carcinoma
  Glioblastoma multiforme
  Nervous system inflammation
  Periodontitis
  Pneumocystis pneumonia
  Psychotic disorder
  Rectal carcinoma
  Rheumatoid arthritis
  Schizophrenia
  Skin disease
• UniProt ID: CCRL2_HUMAN
• Pfam ID: PF00001
• Sequence:
  MANYTLAPEDEYDVLIEGELESDEAEQCDKYDAQALSAQLVPSLCSAVFVIGVLDNLLVV
  LILVKYKGLKRVENIYLLNLAVSNLCFLLTLPFWAHAGGDPMCKILIGLYFVGLYSETFF
  NCLLTVQRYLVFLHKGNFFSARRRVPCGIITSVLAWVTAILATLPEFVVYKPQMEDQKYK
  CAFSRTPFLPADETFWKHFLTLKMNISVLVLPLFIFTFLYVQMRKTLRFREQRYSLFKLV
  FAIMVVFLLMWAPYNIAFFLSTFKEHFSLSDCKSSYNLDKSVHITKLIATTHCCINPLLY
  AFLDGTFSKYLCRCFHLRSNTPLQPRGQSAQGTSREEPDHSTEV
• Function: Receptor for CCL19 and chemerin/RARRES2. Does not appear to be a signaling receptor, but may have a role in modulating chemokine-triggered immune responses by capturing and internalizing CCL19 or by presenting RARRES2 ligand to CMKLR1, a functional signaling receptors. Plays a critical role for the development of Th2 responses.
• Tissue Specificity: Expressed abundantly in immunal tissues such as spleen, fetal liver, lymph node and bone marrow. Strong expression also in lung and heart. Expressed in almost all hematopoietic cells including monocytes, macrophages, PMNs, T-cells (both CD4+ and CD8+), monocyte-derived iDCs, NK cells, and CD34+ progenitor cells. B-cells expressed isoform 1 but not isoform 2. Up-regulated on synovial neutrophils of rheumatoid arthritis patients.
• 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	REF
Arthritis	DIST1YEL	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Crohn disease	DIS2C5Q8	Definitive	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[5]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[6]
Factor IX deficiency	DISHN9SC	Strong	Altered Expression	[7]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[9]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[10]
Psoriatic arthritis	DISLWTG2	Strong	Genetic Variation	[11]
Skin ulcer	DISDKAQY	Strong	Biomarker	[12]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[13]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[13]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[15]
Periodontitis	DISI9JOI	Limited	Altered Expression	[16]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[17]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[18]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[19]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[3]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[18]
Skin disease	DISDW8R6	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of C-C chemokine receptor-like 2 (CCRL2).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of C-C chemokine receptor-like 2 (CCRL2).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of C-C chemokine receptor-like 2 (CCRL2).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of C-C chemokine receptor-like 2 (CCRL2).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of C-C chemokine receptor-like 2 (CCRL2).	[25]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of C-C chemokine receptor-like 2 (CCRL2).	[26]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of C-C chemokine receptor-like 2 (CCRL2).	[27]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of C-C chemokine receptor-like 2 (CCRL2).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of C-C chemokine receptor-like 2 (CCRL2).	[30]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of C-C chemokine receptor-like 2 (CCRL2).	[31]

1 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 C-C chemokine receptor-like 2 (CCRL2).	[29]

References

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• [2] CRAM-A indicates IFN--associated inflammatory response in breast cancer.Mol Immunol. 2015 Dec;68(2 Pt C):692-8. doi: 10.1016/j.molimm.2015.10.019. Epub 2015 Nov 10.
• [3] A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility.Nat Genet. 2010 Jun;42(6):515-9. doi: 10.1038/ng.583. Epub 2010 May 9.
• [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] DNA aneuploidy assessment of the effectiveness of hyperthermo-chemo-radiotherapy for esophageal carcinoma.Cancer. 1989 May 15;63(10):1951-5. doi: 10.1002/1097-0142(19890515)63:10<1951::aid-cncr2820631014>3.0.co;2-4.
• [6] Genetic association of the CCR5 region with lipid levels in at-risk cardiovascular patients.Circ Cardiovasc Genet. 2010 Apr;3(2):162-8. doi: 10.1161/CIRCGENETICS.109.897793. Epub 2010 Feb 3.
• [7] Gene therapy for hemophilia B with liver-specific element mediated by Rep-RBE site-specific integration system.J Cardiovasc Pharmacol. 2015 Feb;65(2):153-9. doi: 10.1097/FJC.0000000000000172.
• [8] The Atypical Receptor CCRL2 Is Essential for Lung Cancer Immune Surveillance.Cancer Immunol Res. 2019 Nov;7(11):1775-1788. doi: 10.1158/2326-6066.CIR-19-0168. Epub 2019 Sep 4.
• [9] Chemokine (CC-motif) receptor-like 2 mRNA is expressed in hepatic stellate cells and is positively associated with characteristics of non-alcoholic steatohepatitis in mice and men.Exp Mol Pathol. 2017 Aug;103(1):1-8. doi: 10.1016/j.yexmp.2017.06.001. Epub 2017 Jun 15.
• [10] CCHCR1 is up-regulated in skin cancer and associated with EGFR expression.PLoS One. 2009 Jun 24;4(6):e6030. doi: 10.1371/journal.pone.0006030.
• [11] Clinical associations of the risk alleles of HLA-Cw6 and CCHCR1*WWCC in psoriasis.Acta Derm Venereol. 2007;87(2):127-34. doi: 10.2340/00015555-0184.
• [12] HCR, a candidate gene for psoriasis, is expressed differently in psoriasis and other hyperproliferative skin disorders and is downregulated by interferon-gamma in keratinocytes.J Invest Dermatol. 2003 Dec;121(6):1360-4. doi: 10.1046/j.1523-1747.2003.12642.x.
• [13] DNA Repair Capacity in Multiple Pathways Predicts Chemoresistance in Glioblastoma Multiforme.Cancer Res. 2017 Jan 1;77(1):198-206. doi: 10.1158/0008-5472.CAN-16-1151. Epub 2016 Oct 28.
• [14] Senescent fibroblast-derived Chemerin promotes squamous cell carcinoma migration.Oncotarget. 2016 Dec 13;7(50):83554-83569. doi: 10.18632/oncotarget.13446.
• [15] 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.
• [16] Evaluation of chemerin and its receptors, ChemR23 and CCRL2, in gingival tissues with healthy and periodontitis.Odontology. 2018 Jan;106(1):29-36. doi: 10.1007/s10266-017-0297-2. Epub 2017 Feb 23.
• [17] Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia.PLoS Genet. 2011 Oct;7(10):e1002328. doi: 10.1371/journal.pgen.1002328. Epub 2011 Oct 27.
• [18] Prediction of Violence, Suicide Behaviors and Suicide Ideation in a Sample of Institutionalized Offenders With Schizophrenia and Other Psychosis.Front Psychol. 2018 Aug 7;9:1385. doi: 10.3389/fpsyg.2018.01385. eCollection 2018.
• [19] Analysis of histological therapeutic effect, apoptosis rate and p53 status after combined treatment with radiation, hyperthermia and 5-fluorouracil suppositories for advanced rectal cancers.Br J Cancer. 1998;77(1):159-66. doi: 10.1038/bjc.1998.25.
• [20] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [21] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [22] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [23] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [24] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [28] 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.
• [29] 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.
• [30] Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression. Cell Rep. 2015 Sep 29;12(12):1986-96. doi: 10.1016/j.celrep.2015.08.046. Epub 2015 Sep 17.
• [31] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.