Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWK51S)

• DOT Name: Cytokine-dependent hematopoietic cell linker (CLNK)
• Synonyms: Mast cell immunoreceptor signal transducer
• Gene Name: CLNK
• Related Disease:
  Fatty liver disease
  Gout
  Liver cirrhosis
  Vitiligo
• UniProt ID: CLNK_HUMAN
• Pfam ID: PF00017
• Sequence:
  MNRQGNRKTTKEGSNDLKFQNFSLPKNRSWPRINSATGQYQRMNKPLLDWERNFAAVLDG
  AKGHSDDDYDDPELRMEETWQSIKILPARPIKESEYADTHYFKVAMDTPLPLDTRTSISI
  GQPTWNTQTRLERVDKPISKDVRSQNIKGDASVRKNKIPLPPPRPLITLPKKYQPLPPEP
  ESSRPPLSQRHTFPEVQRMPSQISLRDLSEVLEAEKVPHNQRKPESTHLLENQNTQEIPL
  AISSSSFTTSNHSVQNRDHRGGMQPCSPQRCQPPASCSPHENILPYKYTSWRPPFPKRSD
  RKDVQHNEWYIGEYSRQAVEEAFMKENKDGSFLVRDCSTKSKEEPYVLAVFYENKVYNVK
  IRFLERNQQFALGTGLRGDEKFDSVEDIIEHYKNFPIILIDGKDKTGVHRKQCHLTQPLP
  LTRHLLPL
• Function: An adapter protein which plays a role in the regulation of immunoreceptor signaling, including PLC-gamma-mediated B-cell antigen receptor (BCR) signaling and FC-epsilon R1-mediated mast cell degranulation. Together with FGR, it acts as a negative regulator of natural killer cell-activating receptors and inhibits interferon-gamma production. Acts as a positive regulator of both T-cell receptor and natural killer T (NKT) cell receptor signaling in CD4-positive NKT cells. Together with MAP4K1, it enhances CD3-triggered activation of T-cells and subsequent IL2 production. May be involved in tumor necrosis factor induced cell death by promoting reactive oxidative species generation, and MLKL oligomerization, ultimately leading to necrosis. Involved in phosphorylation of LAT. May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[1]
Gout	DISHC0U7	Strong	Genetic Variation	[2]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[3]
Vitiligo	DISR05SL	Strong	Biomarker	[4]

4 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 Cytokine-dependent hematopoietic cell linker (CLNK).	[5]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Cytokine-dependent hematopoietic cell linker (CLNK).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cytokine-dependent hematopoietic cell linker (CLNK).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Cytokine-dependent hematopoietic cell linker (CLNK).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cytokine-dependent hematopoietic cell linker (CLNK).	[6]

References

• [1] The association of IL28B genotype with the histological features of chronic hepatitis C is HCV genotype dependent.Int J Mol Sci. 2014 Apr 25;15(5):7213-24. doi: 10.3390/ijms15057213.
• [2] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [3] Hyporesponsiveness to PegIFN2B plus ribavirin in patients with hepatitis C-related advanced fibrosis.J Hepatol. 2012 Feb;56(2):341-7. doi: 10.1016/j.jhep.2011.05.022. Epub 2011 Jul 12.
• [4] Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.Nat Genet. 2012 May 6;44(6):676-80. doi: 10.1038/ng.2272.
• [5] 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.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] 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.
• [8] 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.