Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBIT23O)

• DOT Name: Myotubularin-related protein 3 (MTMR3)
• Synonyms: EC 3.1.3.48; FYVE domain-containing dual specificity protein phosphatase 1; FYVE-DSP1; Phosphatidylinositol-3,5-bisphosphate 3-phosphatase; EC 3.1.3.95; Phosphatidylinositol-3-phosphate phosphatase; EC 3.1.3.64; Zinc finger FYVE domain-containing protein 10
• Gene Name: MTMR3
• Related Disease:
  Rheumatoid arthritis
  Breast cancer
  Breast carcinoma
  Crohn disease
  Dental caries
  Gastric cancer
  Glioma
  Herpes simplex infection
  Inflammatory bowel disease
  Isolated cleft lip
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Non-insulin dependent diabetes
  Oral cancer
  Stomach cancer
  Systemic lupus erythematosus
  Acute myelogenous leukaemia
  Colon cancer
  Colon carcinoma
  Neoplasm
  Triple negative breast cancer
  Advanced cancer
  Colorectal carcinoma
  IgA nephropathy
  Lupus nephritis
• UniProt ID: MTMR3_HUMAN
• EC Number: 3.1.3.48; 3.1.3.64; 3.1.3.95
• Pfam ID: PF01363 ; PF06602
• Sequence:
  MDEETRHSLECIQANQIFPRKQLIREDENLQVPFLELHGESTEFVGRAEDAIIALSNYRL
  HIKFKESLVNVPLQLIESVECRDIFQLHLTCKDCKVIRCQFSTFEQCQEWLKRLNNAIRP
  PAKIEDLFSFAYHAWCMEVYASEKEQHGDLCRPGEHVTSRFKNEVERMGFDMNNAWRISN
  INEKYKLCGSYPQELIVPAWITDKELESVSSFRSWKRIPAVIYRHQSNGAVIARCGQPEV
  SWWGWRNADDEHLVQSVAKACASDSRSSGSKLSTRNTSRDFPNGGDLSDVEFDSSLSNAS
  GAESLAIQPQKLLILDARSYAAAVANRAKGGGCECPEYYPNCEVVFMGMANIHSIRRSFQ
  SLRLLCTQMPDPGNWLSALESTKWLHHLSVLLKSALLVVHAVDQDQRPVLVHCSDGWDRT
  PQIVALAKLLLDPYYRTIEGFQVLVEMEWLDFGHKFADRCGHGENSDDLNERCPVFLQWL
  DCVHQLQRQFPCSFEFNEAFLVKLVQHTYSCLFGTFLCNNAKERGEKHTQERTCSVWSLL
  RAGNKAFKNLLYSSQSEAVLYPVCHVRNLMLWSAVYLPCPSPTTPVDDSCAPYPAPGTSP
  DDPPLSRLPKTRSYDNLTTACDNTVPLASRRCSDPSLNEKWQEHRRSLELSSLAGPGEDP
  LSADSLGKPTRVPGGAELSVAAGVAEGQMENILQEATKEESGVEEPAHRAGIEIQEGKED
  PLLEKESRRKTPEASAIGLHQDPELGDAALRSHLDMSWPLFSQGISEQQSGLSVLLSSLQ
  VPPRGEDSLEVPVEQFRIEEIAEGREEAVLPIPVDAKVGYGTSQSCSLLPSQVPFETRGP
  NVDSSTDMLVEDKVKSVSGPQGHHRSCLVNSGKDRLPQTMEPSPSETSLVERPQVGSVVH
  RTSLGSTLSLTRSPCALPLAECKEGLVCNGAPETENRASEQPPGLSTLQMYPTPNGHCAN
  GEAGRSKDSLSRQLSAMSCSSAHLHSRNLHHKWLHSHSGRPSATSSPDQPSRSHLDDDGM
  SVYTDTIQQRLRQIESGHQQEVETLKKQVQELKSRLESQYLTSSLHFNGDFGDEVTSIPD
  SESNLDQNCLSRCSTEIFSEASWEQVDKQDTEMTRWLPDHLAAHCYACDSAFWLASRKHH
  CRNCGNVFCSSCCNQKVPVPSQQLFEPSRVCKSCYSSLHPTSSSIDLELDKPIAATSN
• Function: Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. May also dephosphorylate proteins phosphorylated on Ser, Thr, and Tyr residues.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
  Autophagy - animal (hsa04140)
• Reactome Pathway:
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
  Macroautophagy (R-HSA-1632852)
• BioCyc Pathway: MetaCyc:HS02045-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[3]
Dental caries	DISRBCMD	Strong	Genetic Variation	[4]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[5]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[8]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[9]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[10]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[10]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[12]
Oral cancer	DISLD42D	Strong	Altered Expression	[13]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[5]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[14]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[15]
Colon cancer	DISVC52G	moderate	Biomarker	[2]
Colon carcinoma	DISJYKUO	moderate	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Triple negative breast cancer	DISAMG6N	moderate	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[16]
IgA nephropathy	DISZ8MTK	Limited	Biomarker	[17]
Lupus nephritis	DISCVGPZ	Limited	Biomarker	[14]

4 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 Myotubularin-related protein 3 (MTMR3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Myotubularin-related protein 3 (MTMR3).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Myotubularin-related protein 3 (MTMR3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Myotubularin-related protein 3 (MTMR3).	[26]

5 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 Myotubularin-related protein 3 (MTMR3).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myotubularin-related protein 3 (MTMR3).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myotubularin-related protein 3 (MTMR3).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Myotubularin-related protein 3 (MTMR3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Myotubularin-related protein 3 (MTMR3).	[24]

References

• [1] Association of MTMR3 rs12537 at miR-181a binding site with rheumatoid arthritis and systemic lupus erythematosus risk in Egyptian patients.Sci Rep. 2019 Aug 23;9(1):12299. doi: 10.1038/s41598-019-48770-5.
• [2] MTMR3 is upregulated in patients with breast cancer and regulates proliferation, cell cycle progression and autophagy in breast cancer cells.Oncol Rep. 2019 Nov;42(5):1915-1923. doi: 10.3892/or.2019.7292. Epub 2019 Aug 23.
• [3] Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress.Autophagy. 2013 Dec;9(12):2046-55. doi: 10.4161/auto.26337. Epub 2013 Nov 14.
• [4] Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.Nat Commun. 2019 Jun 24;10(1):2773. doi: 10.1038/s41467-019-10630-1.
• [5] Genetic polymorphism at miR-181a binding site contributes to gastric cancer susceptibility.Carcinogenesis. 2012 Dec;33(12):2377-83. doi: 10.1093/carcin/bgs292. Epub 2012 Sep 12.
• [6] MicroRNA 10a induces glioma tumorigenesis by targeting myotubularin-related protein 3 and regulating the Wnt/-catenin signaling pathway.FEBS J. 2019 Jul;286(13):2577-2592. doi: 10.1111/febs.14824. Epub 2019 Apr 11.
• [7] PtdIns3P phosphatases MTMR3 and MTMR4 negatively regulate innate immune responses to DNA through modulating STING trafficking.J Biol Chem. 2019 May 24;294(21):8412-8423. doi: 10.1074/jbc.RA118.005731. Epub 2019 Apr 3.
• [8] MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation.Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10461-6. doi: 10.1073/pnas.1501752112. Epub 2015 Aug 3.
• [9] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [10] A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese.Nat Genet. 2011 Jul 3;43(8):792-6. doi: 10.1038/ng.875.
• [11] PIKfyve, MTMR3 and their product PtdIns5P regulate cancer cell migration and invasion through activation of Rac1.Biochem J. 2014 Aug 1;461(3):383-90. doi: 10.1042/BJ20140132.
• [12] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [13] MiR-99a exerts anti-metastasis through inhibiting myotubularin-related protein 3 expression in oral cancer.Oral Dis. 2014 Apr;20(3):e65-75. doi: 10.1111/odi.12133. Epub 2013 Jun 4.
• [14] Podocytes and autophagy: a potential therapeutic target in lupus nephritis.Autophagy. 2019 May;15(5):908-912. doi: 10.1080/15548627.2019.1580512. Epub 2019 Feb 17.
• [15] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [16] Mutational analysis of mononucleotide repeats in dual specificity tyrosine phosphatase genes in gastric and colon carcinomas with microsatellite instability.APMIS. 2010 May;118(5):389-93. doi: 10.1111/j.1600-0463.2010.02612.x.
• [17] Three SNPs of FCRL3 and one SNP of MTMR3 are associated with immunoglobulin A nephropathy risk.Immunobiology. 2020 Jan;225(1):151869. doi: 10.1016/j.imbio.2019.11.004. Epub 2019 Nov 18.
• [18] 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.
• [19] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] 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.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] 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.