Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGGC20G)

• DOT Name: T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD4)
• Synonyms: TIMD-4; T-cell immunoglobulin mucin receptor 4; TIM-4; T-cell membrane protein 4
• Gene Name: TIMD4
• Related Disease:
  Allergic rhinitis
  Hepatocellular carcinoma
  Asthma
  Atopic dermatitis
  Autoimmune disease
  Cardiovascular disease
  Clear cell renal carcinoma
  Colorectal carcinoma
  Food allergy
  Hepatitis
  Lung cancer
  Lung carcinoma
  Malaria
  Non-alcoholic fatty liver disease
  Non-small-cell lung cancer
  Plasmodium falciparum malaria
  Systemic lupus erythematosus
  Immune system disorder
  Neoplasm
  Non-insulin dependent diabetes
  Ebola virus infection
  Stroke
  Type-1/2 diabetes
• UniProt ID: TIMD4_HUMAN
• PDB ID: 5DZN; 5F7F; 5F7H
• Pfam ID: PF07686
• Sequence:
  MSKEPLILWLMIEFWWLYLTPVTSETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCP
  YSGCKEALIRTDGMRVTSRKSAKYRLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWF
  NDVKINVRLNLQRASTTTHRTATTTTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTG
  TPLQMTTIAVFTTANTCLSLTPSTLPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSV
  ESTSADTVLLTSKESKVWDLPSTSHVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMD
  GIPMSMKNEMPISQLLMIIAPSLGFVLFALFVAFLLRGKLMETYCSQKHTRLDYIGDSKN
  VLNDVQHGREDEDGLFTL
• Function: Phosphatidylserine receptor that plays different role in immune response including phagocytosis of apoptotic cells and T-cell regulation. Controls T-cell activation in a bimodal fashion, decreasing the activation of naive T-cells by inducing cell cycle arrest, while increasing proliferation of activated T-cells by activating AKT1 and ERK1/2 phosphorylations and subsequent signaling pathways. Also plays a role in efferocytosis which is the process by which apoptotic cells are removed by phagocytic cells. Mechanistically, promotes the engulfment of apoptotic cells or exogenous particles by securing them to phagocytes through direct binding to phosphatidylserine present on apoptotic cells, while other engulfment receptors such as MERTK efficiently recognize apoptotic cells and mediate their ingestion. Additionally, promotes autophagy process by suppressing NLRP3 inflammasome activity via activation of LKB1/PRKAA1 pathway in a phosphatidylserine-dependent mechanism; (Microbial infection) Plays a positive role in exosome-mediated trafficking of HIV-1 virus and its entry into immune cells.
• KEGG Pathway: Efferocytosis (hsa04148)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Definitive	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Asthma	DISW9QNS	Strong	Biomarker	[3]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Food allergy	DISMQ1BP	Strong	Biomarker	[3]
Hepatitis	DISXXX35	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Malaria	DISQ9Y50	Strong	Genetic Variation	[11]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[10]
Plasmodium falciparum malaria	DIS3Q9KF	Strong	Genetic Variation	[11]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[12]
Immune system disorder	DISAEGPH	moderate	Biomarker	[13]
Neoplasm	DISZKGEW	moderate	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	moderate	Biomarker	[13]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[14]
Stroke	DISX6UHX	Limited	Altered Expression	[15]
Type-1/2 diabetes	DISIUHAP	Limited	Altered Expression	[16]

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 T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD4).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD4).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD4).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD4).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of T-cell immunoglobulin and mucin domain-containing protein 4 (TIMD4).	[20]

References

• [1] Vitamin D regulates immunoglobulin mucin domain molecule-4 expression in dendritic cells.Clin Exp Allergy. 2017 May;47(5):656-664. doi: 10.1111/cea.12894. Epub 2017 Feb 28.
• [2] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [3] The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoimmunity.Allergy Asthma Proc. 2013 Jan-Feb;34(1):e21-6. doi: 10.2500/aap.2013.34.3646.
• [4] Genetic association studies between the T cell immunoglobulin mucin (TIM) gene locus and childhood atopic dermatitis.Int Arch Allergy Immunol. 2006;141(4):331-6. doi: 10.1159/000095459. Epub 2006 Aug 29.
• [5] Novel insights into Tim-4 function in autoimmune diseases.Autoimmunity. 2015 Jun;48(4):189-95. doi: 10.3109/08916934.2014.983266. Epub 2014 Nov 19.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] The significance of TIMD4 expression in clear cell renal cell carcinoma.Med Mol Morphol. 2017 Dec;50(4):220-226. doi: 10.1007/s00795-017-0164-9. Epub 2017 Jun 19.
• [8] RETRACTED: Tim-4 promotes the growth of colorectal cancer by activating angiogenesis and recruiting tumor-associated macrophages via the PI3K/AKT/mTOR signaling pathway.Cancer Lett. 2018 Nov 1;436:119-128. doi: 10.1016/j.canlet.2018.08.012. Epub 2018 Aug 14.
• [9] Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPK Pathway in Macrophages.J Immunol. 2019 Aug 15;203(4):990-1000. doi: 10.4049/jimmunol.1900117. Epub 2019 Jul 1.
• [10] TIM-4 promotes the growth of non-small-cell lung cancer in a RGD motif-dependent manner.Br J Cancer. 2015 Nov 17;113(10):1484-92. doi: 10.1038/bjc.2015.323. Epub 2015 Oct 29.
• [11] Significant association between TIM1 promoter polymorphisms and protection against cerebral malaria in Thailand.Ann Hum Genet. 2008 May;72(Pt 3):327-36. doi: 10.1111/j.1469-1809.2007.00424.x. Epub 2008 Feb 19.
• [12] Promoter polymorphisms of the TIM-4 gene are correlated with disease activity in patients with systemic lupus erythematosus.Int J Immunogenet. 2017 Jun;44(3):122-128. doi: 10.1111/iji.12316. Epub 2017 Mar 31.
• [13] Increased T cell immunoglobulin and mucin domain containing 4 (TIM-4) is negatively correlated with serum concentrations of interleukin-1 in type 2 diabetes.J Diabetes. 2016 Mar;8(2):199-205. doi: 10.1111/1753-0407.12276. Epub 2015 Apr 9.
• [14] TIM-family proteins inhibit HIV-1 release.Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):E3699-707. doi: 10.1073/pnas.1404851111. Epub 2014 Aug 18.
• [15] Tim-4 expression increases in ischemic stroke patients and is associated with poor outcome.J Neuroimmunol. 2018 Mar 15;316:1-6. doi: 10.1016/j.jneuroim.2017.11.017. Epub 2017 Dec 2.
• [16] TIM4 Regulates the Anti-Islet Th2 Alloimmune Response.Cell Transplant. 2015;24(8):1599-1614. doi: 10.3727/096368914X678571. Epub 2014 Mar 7.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] 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.
• [21] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.