Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6345CH)

• DOT Name: FYN-binding protein 1 (FYB1)
• Synonyms: Adhesion and degranulation promoting adaptor protein; ADAP; FYB-120/130; p120/p130; FYN-T-binding protein; SLAP-130; SLP-76-associated phosphoprotein
• Gene Name: FYB1
• Related Disease:
  Allergic contact dermatitis
  Breast cancer
  Breast carcinoma
  Dilated cardiomyopathy 1A
  Ductal breast carcinoma in situ
  Hepatitis B virus infection
  Influenza
  Inherited bleeding disorder, platelet-type
  Major depressive disorder
  Mood disorder
  Nervous system inflammation
  Plasmodium vivax malaria
  Progressive multifocal leukoencephalopathy
  Thrombocytopenia
  Thrombocytopenia 3
  Type-1 diabetes
• UniProt ID: FYB1_HUMAN
• PDB ID: 1RI9; 2GTJ; 2GTO
• Pfam ID: PF14603 ; PF07653
• Sequence:
  MAKYNTGGNPTEDVSVNSRPFRVTGPNSSSGIQARKNLFNNQGNASPPAGPSNVPKFGSP
  KPPVAVKPSSEEKPDKEPKPPFLKPTGAGQRFGTPASLTTRDPEAKVGFLKPVGPKPINL
  PKEDSKPTFPWPPGNKPSLHSVNQDHDLKPLGPKSGPTPPTSENEQKQAFPKLTGVKGKF
  MSASQDLEPKPLFPKPAFGQKPPLSTENSHEDESPMKNVSSSKGSPAPLGVRSKSGPLKP
  AREDSENKDHAGEISSLPFPGVVLKPAASRGGPGLSKNGEEKKEDRKIDAAKNTFQSKIN
  QEELASGTPPARFPKAPSKLTVGGPWGQSQEKEKGDKNSATPKQKPLPPLFTLGPPPPKP
  NRPPNVDLTKFHKTSSGNSTSKGQTSYSTTSLPPPPPSHPASQPPLPASHPSQPPVPSLP
  PRNIKPPFDLKSPVNEDNQDGVTHSDGAGNLDEEQDSEGETYEDIEASKEREKKREKEEK
  KRLELEKKEQKEKEKKEQEIKKKFKLTGPIQVIHLAKACCDVKGGKNELSFKQGEQIEII
  RITDNPEGKWLGRTARGSYGYIKTTAVEIDYDSLKLKKDSLGAPSRPIEDDQEVYDDVAE
  QDDISSHSQSGSGGIFPPPPDDDIYDGIEEEDADDGFPAPPKQLDMGDEVYDDVDTSDFP
  VSSAEMSQGTNVGKAKTEEKDLKKLKKQEKEEKDFRKKFKYDGEIRVLYSTKVTTSITSK
  KWGTRDLQVKPGESLEVIQTTDDTKVLCRNEEGKYGYVLRSYLADNDGEIYDDIADGCIY
  DND
• Function: Acts as an adapter protein of the FYN and LCP2 signaling cascades in T-cells. May play a role in linking T-cell signaling to remodeling of the actin cytoskeleton. Modulates the expression of IL2. Involved in platelet activation. Prevents the degradation of SKAP1 and SKAP2. May be involved in high affinity immunoglobulin epsilon receptor signaling in mast cells.
• Tissue Specificity: Expressed in hematopoietic tissues such as myeloid and T-cells, spleen and thymus. Not expressed in B-cells, nor in non-lymphoid tissues.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  Signal regulatory protein family interactions (R-HSA-391160)
  Generation of second messenger molecules (R-HSA-202433)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic contact dermatitis	DISFFVF9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[2]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Genetic Variation	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[6]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[6]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[7]
Plasmodium vivax malaria	DISPU3H9	Strong	Genetic Variation	[8]
Progressive multifocal leukoencephalopathy	DISX02WS	Strong	Genetic Variation	[9]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[7]
Thrombocytopenia 3	DIS75MJX	Strong	Autosomal recessive	[10]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of FYN-binding protein 1 (FYB1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of FYN-binding protein 1 (FYB1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of FYN-binding protein 1 (FYB1).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of FYN-binding protein 1 (FYB1).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of FYN-binding protein 1 (FYB1).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of FYN-binding protein 1 (FYB1).	[18]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of FYN-binding protein 1 (FYB1).	[19]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of FYN-binding protein 1 (FYB1).	[20]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of FYN-binding protein 1 (FYB1).	[22]

3 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 FYN-binding protein 1 (FYB1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of FYN-binding protein 1 (FYB1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of FYN-binding protein 1 (FYB1).	[23]

References

• [1] Gene transcripts as potential diagnostic markers for allergic contact dermatitis.Contact Dermatitis. 2005 Aug;53(2):100-6. doi: 10.1111/j.0105-1873.2005.00658.x.
• [2] Identification of aberrant gene expression during breast ductal carcinoma in situ progression to invasive ductal carcinoma.J Int Med Res. 2020 Jan;48(1):300060518815364. doi: 10.1177/0300060518815364. Epub 2019 Feb 3.
• [3] Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?.Bull World Health Organ. 2010 Jan;88(1):66-73. doi: 10.2471/BLT.08.065722. Epub 2009 Oct 23.
• [4] The Immune Adaptor ADAP Regulates Reciprocal TGF-1-Integrin Crosstalk to Protect from Influenza Virus Infection.PLoS Pathog. 2015 Apr 24;11(4):e1004824. doi: 10.1371/journal.ppat.1004824. eCollection 2015 Apr.
• [5] ADAP deficiency impairs megakaryocyte polarization with ectopic proplatelet release and causes microthrombocytopenia.Blood. 2018 Aug 9;132(6):635-646. doi: 10.1182/blood-2018-01-829259. Epub 2018 Jun 27.
• [6] Analysis of 23andMe antidepressant efficacy survey data: implication of circadian rhythm and neuroplasticity in bupropion response.Transl Psychiatry. 2016 Sep 13;6(9):e889. doi: 10.1038/tp.2016.171.
• [7] Immune Cell-Type Specific Ablation of Adapter Protein ADAP Differentially Modulates EAE.Front Immunol. 2019 Oct 1;10:2343. doi: 10.3389/fimmu.2019.02343. eCollection 2019.
• [8] Duffy blood group genotypes among malaria Plasmodium vivax patients of Baoulch population in Southeastern Iran.Asian Pac J Trop Med. 2014 Mar;7(3):206-7. doi: 10.1016/S1995-7645(14)60021-3.
• [9] PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells.J Biol Chem. 2001 Jun 22;276(25):22375-81. doi: 10.1074/jbc.M011683200. Epub 2001 Apr 11.
• [10] Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report. BMC Med Genet. 2014 Dec 17;15:135. doi: 10.1186/s12881-014-0135-0.
• [11] Short Communication FYB polymorphisms in Brazilian patients with type I diabetes mellitus and autoimmune polyglandular syndrome type III.Genet Mol Res. 2015 Jan 15;14(1):29-33. doi: 10.4238/2015.January.15.4.
• [12] Immediate up-regulation of the calcium-binding protein S100P and its involvement in the cytokinin-induced differentiation of human myeloid leukemia cells. Biochim Biophys Acta. 2005 Sep 10;1745(2):156-65.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [16] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [17] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [18] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [19] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [20] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [21] 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.
• [22] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [23] 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.