Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSSPF6F)

• DOT Name: B-cell linker protein (BLNK)
• Synonyms: B-cell adapter containing a SH2 domain protein; B-cell adapter containing a Src homology 2 domain protein; Cytoplasmic adapter protein; Src homology 2 domain-containing leukocyte protein of 65 kDa; SLP-65
• Gene Name: BLNK
• Related Disease:
  Adult lymphoma
  Agammaglobulinemia 4, autosomal recessive
  Pediatric lymphoma
  Acute lymphocytic leukaemia
  Agammaglobulinemia
  Alzheimer disease
  Anaplastic large cell lymphoma
  Arthritis
  B-cell acute lymphoblastic leukaemia
  B-cell lymphoma
  Bladder cancer
  Bruton-type agammaglobulinemia
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  IgA nephropathy
  Neoplasm
  Progressive multifocal leukoencephalopathy
  Urinary bladder cancer
  Urinary bladder neoplasm
  Waldenstrom macroglobulinemia
  Epstein barr virus infection
  Lymphoma
  Autosomal agammaglobulinemia
  Enterovirus infection
  leukaemia
  Leukemia
  Lymphoid leukemia
  Small lymphocytic lymphoma
• UniProt ID: BLNK_HUMAN
• PDB ID: 6YLU
• Pfam ID: PF00017
• Sequence:
  MDKLNKITVPASQKLRQLQKMVHDIKNNEGGIMNKIKKLKVKAPPSVPRRDYASESPADE
  EEQWSDDFDSDYENPDEHSDSEMYVMPAEENADDSYEPPPVEQETRPVHPALPFARGEYI
  DNRSSQRHSPPFSKTLPSKPSWPSEKARLTSTLPALTALQKPQVPPKPKGLLEDEADYVV
  PVEDNDENYIHPTESSSPPPEKAPMVNRSTKPNSSTPASPPGTASGRNSGAWETKSPPPA
  APSPLPRAGKKPTTPLKTTPVASQQNASSVCEEKPIPAERHRGSSHRQEAVQSPVFPPAQ
  KQIHQKPIPLPRFTEGGNPTVDGPLPSFSSNSTISEQEAGVLCKPWYAGACDRKSAEEAL
  HRSNKDGSFLIRKSSGHDSKQPYTLVVFFNKRVYNIPVRFIEATKQYALGRKKNGEEYFG
  SVAEIIRNHQHSPLVLIDSQNNTKDSTRLKYAVKVS
• Function: Functions as a central linker protein, downstream of the B-cell receptor (BCR), bridging the SYK kinase to a multitude of signaling pathways and regulating biological outcomes of B-cell function and development. Plays a role in the activation of ERK/EPHB2, MAP kinase p38 and JNK. Modulates AP1 activation. Important for the activation of NF-kappa-B and NFAT. Plays an important role in BCR-mediated PLCG1 and PLCG2 activation and Ca(2+) mobilization and is required for trafficking of the BCR to late endosomes. However, does not seem to be required for pre-BCR-mediated activation of MAP kinase and phosphatidyl-inositol 3 (PI3) kinase signaling. May be required for the RAC1-JNK pathway. Plays a critical role in orchestrating the pro-B cell to pre-B cell transition. May play an important role in BCR-induced B-cell apoptosis.
• Tissue Specificity: Expressed in B-cell lineage and fibroblast cell lines (at protein level). Highest levels of expression in the spleen, with lower levels in the liver, kidney, pancreas, small intestines and colon.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  B cell receptor sig.ling pathway (hsa04662)
  Epstein-Barr virus infection (hsa05169)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Potential therapeutics for SARS (R-HSA-9679191)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  Regulation of signaling by CBL (R-HSA-912631)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Definitive	Biomarker	[1]
Agammaglobulinemia 4, autosomal recessive	DIS9X953	Definitive	Autosomal recessive	[2]
Pediatric lymphoma	DIS51BK2	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[3]
Agammaglobulinemia	DISXMS80	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[6]
Arthritis	DIST1YEL	Strong	Biomarker	[4]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Biomarker	[7]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[8]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Bruton-type agammaglobulinemia	DISQ5ZYP	Strong	Genetic Variation	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[11]
Colon cancer	DISVC52G	Strong	Biomarker	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Waldenstrom macroglobulinemia	DIS9O23I	Strong	Altered Expression	[15]
Epstein barr virus infection	DISOO0WT	moderate	Posttranslational Modification	[16]
Lymphoma	DISN6V4S	moderate	Biomarker	[1]
Autosomal agammaglobulinemia	DISRW8BT	Supportive	Autosomal dominant	[17]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[4]
leukaemia	DISS7D1V	Limited	Altered Expression	[18]
Leukemia	DISNAKFL	Limited	Altered Expression	[18]
Lymphoid leukemia	DIS65TYQ	Limited	Altered Expression	[18]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[19]

2 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 B-cell linker protein (BLNK).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of B-cell linker protein (BLNK).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of B-cell linker protein (BLNK).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of B-cell linker protein (BLNK).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of B-cell linker protein (BLNK).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of B-cell linker protein (BLNK).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of B-cell linker protein (BLNK).	[21]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of B-cell linker protein (BLNK).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of B-cell linker protein (BLNK).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of B-cell linker protein (BLNK).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of B-cell linker protein (BLNK).	[29]

References

• [1] The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells.Oncogene. 2006 Aug 17;25(36):5056-62. doi: 10.1038/sj.onc.1209510. Epub 2006 Mar 27.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] B Cell Linker Protein (BLNK) Is a Selective Target of Repression by PAX5-PML Protein in the Differentiation Block That Leads to the Development of Acute Lymphoblastic Leukemia.J Biol Chem. 2016 Feb 26;291(9):4723-31. doi: 10.1074/jbc.M115.637835. Epub 2015 Dec 24.
• [4] Enteroviral Infection in a Patient with BLNK Adaptor Protein Deficiency.J Clin Immunol. 2015 May;35(4):356-60. doi: 10.1007/s10875-015-0164-2. Epub 2015 Apr 17.
• [5] Vincamine Alleviates Amyloid- 25-35 Peptides-induced Cytotoxicity in PC12 Cells.Pharmacogn Mag. 2017 Jan-Mar;13(49):123-128. doi: 10.4103/0973-1296.196309.
• [6] The histologic, immunohistochemical, and genetic features of classical Hodgkin lymphoma and anaplastic large cell lymphoma with aberrant T-cell/B-cell antigen expression.Hum Pathol. 2019 Feb;84:309-320. doi: 10.1016/j.humpath.2018.10.003. Epub 2018 Oct 17.
• [7] Deficiency of the adaptor SLP-65 in pre-B-cell acute lymphoblastic leukaemia.Nature. 2003 May 22;423(6938):452-6. doi: 10.1038/nature01608.
• [8] The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop.Blood. 2013 Dec 19;122(26):4220-9. doi: 10.1182/blood-2012-12-473090. Epub 2013 Oct 29.
• [9] Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer.J Exp Clin Cancer Res. 2017 Jun 9;36(1):77. doi: 10.1186/s13046-017-0542-0.
• [10] Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia.Protein Sci. 2000 Dec;9(12):2377-85. doi: 10.1110/ps.9.12.2377.
• [11] Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic leukemia.Leukemia. 2004 May;18(5):922-5. doi: 10.1038/sj.leu.2403349.
• [12] 2'-benzoyloxycinnamaldehyde induces apoptosis in human carcinoma via reactive oxygen species.J Biol Chem. 2004 Feb 20;279(8):6911-20. doi: 10.1074/jbc.M309708200. Epub 2003 Dec 3.
• [13] Increase in B-cell-activation factor (BAFF) and IFN-gamma productions by tonsillar mononuclear cells stimulated with deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) in patients with IgA nephropathy.Clin Immunol. 2008 Mar;126(3):260-9. doi: 10.1016/j.clim.2007.11.003. Epub 2008 Jan 14.
• [14] Long Noncoding RNA MIR17HG Promotes Colorectal Cancer Progression via miR-17-5p.Cancer Res. 2019 Oct 1;79(19):4882-4895. doi: 10.1158/0008-5472.CAN-18-3880. Epub 2019 Aug 13.
• [15] Gene expression profiling of B lymphocytes and plasma cells from Waldenstrm's macroglobulinemia: comparison with expression patterns of the same cell counterparts from chronic lymphocytic leukemia, multiple myeloma and normal individuals.Leukemia. 2007 Mar;21(3):541-9. doi: 10.1038/sj.leu.2404520. Epub 2007 Jan 25.
• [16] Epstein-Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module.J Exp Med. 2001 Aug 6;194(3):255-64. doi: 10.1084/jem.194.3.255.
• [17] An essential role for BLNK in human B cell development. Science. 1999 Dec 3;286(5446):1954-7. doi: 10.1126/science.286.5446.1954.
• [18] SLP65 deficiency results in perpetual V(D)J recombinase activity in pre-B-lymphoblastic leukemia and B-cell lymphoma cells.Oncogene. 2006 Aug 24;25(37):5180-6. doi: 10.1038/sj.onc.1209520. Epub 2006 Apr 24.
• [19] Constitutive Phosphorylation of STAT3 by the CK2-BLNK-CD5 Complex.Mol Cancer Res. 2017 May;15(5):610-618. doi: 10.1158/1541-7786.MCR-16-0291. Epub 2017 Jan 27.
• [20] 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.
• [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] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [23] 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.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [27] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.