Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZPWT2N)

• DOT Name: Atypical chemokine receptor 4 (ACKR4)
• Synonyms: C-C chemokine receptor type 11; C-C CKR-11; CC-CKR-11; CCR-11; CC chemokine receptor-like 1; CCRL1; CCX CKR
• Gene Name: ACKR4
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Inflammation
  Pulmonary sarcoidosis
  Sarcoidosis
  Nasopharyngeal carcinoma
  Neoplasm
  Squamous cell carcinoma
• UniProt ID: ACKR4_HUMAN
• Pfam ID: PF00001
• Sequence:
  MALEQNQSTDYYYEENEMNGTYDYSQYELICIKEDVREFAKVFLPVFLTIVFVIGLAGNS
  MVVAIYAYYKKQRTKTDVYILNLAVADLLLLFTLPFWAVNAVHGWVLGKIMCKITSALYT
  LNFVSGMQFLACISIDRYVAVTKVPSQSGVGKPCWIICFCVWMAAILLSIPQLVFYTVND
  NARCIPIFPRYLGTSMKALIQMLEICIGFVVPFLIMGVCYFITARTLMKMPNIKISRPLK
  VLLTVVIVFIVTQLPYNIVKFCRAIDIIYSLITSCNMSKRMDIAIQVTESIALFHSCLNP
  ILYVFMGASFKNYVMKVAKKYGSWRRQRQSVEEFPFDSEGPTEPTSTFSI
• 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 CCL2, CCL8, CCL13, CCL19, CCL21 and CCL25. Chemokine-binding does not activate G-protein-mediated signal transduction but instead induces beta-arrestin recruitment, leading to ligand internalization. Plays an important role in controlling the migration of immune and cancer cells that express chemokine receptors CCR7 and CCR9, by reducing the availability of CCL19, CCL21, and CCL25 through internalization. Negatively regulates CXCR3-induced chemotaxis. Regulates T-cell development in the thymus.
• Tissue Specificity: Predominantly expressed in heart. Lower expression in lung, pancreas, spleen, colon, skeletal muscle and small intestine.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
• Reactome Pathway: Chemokine receptors bind chemokines (R-HSA-380108)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Inflammation	DISJUQ5T	Strong	Altered Expression	[4]
Pulmonary sarcoidosis	DIS1XQCN	Strong	Altered Expression	[4]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[5]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Atypical chemokine receptor 4 (ACKR4).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Atypical chemokine receptor 4 (ACKR4).	[8]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Atypical chemokine receptor 4 (ACKR4).	[9]

References

• [1] CCX-CKR expression in colorectal cancer and patient survival.Int J Biol Markers. 2014 Mar 24;29(1):e40-8. doi: 10.5301/jbm.5000057.
• [2] Effect of functional genetic variants in chemokine decoy receptors on the recurrence risk of breast cancer.Cancer Med. 2018 Nov;7(11):5497-5504. doi: 10.1002/cam4.1823. Epub 2018 Oct 24.
• [3] CC chemokine receptor-like 1 functions as a tumour suppressor by impairing CCR7-related chemotaxis in hepatocellular carcinoma.J Pathol. 2015 Mar;235(4):546-58. doi: 10.1002/path.4450. Epub 2014 Dec 18.
• [4] Expression of CCX CKR in pulmonary sarcoidosis.Inflamm Res. 2006 Oct;55(10):441-5. doi: 10.1007/s00011-006-6019-9.
• [5] Loss of atypical chemokine receptor 4 facilitates C-C motif chemokine ligand 21-mediated tumor growth and invasion in nasopharyngeal carcinoma.Exp Ther Med. 2019 Jan;17(1):613-620. doi: 10.3892/etm.2018.7007. Epub 2018 Nov 23.
• [6] 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.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [9] 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.