Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM9YSIZ)

• DOT Name: Unconventional myosin-Ie (MYO1E)
• Synonyms: Myosin-Ic; Unconventional myosin 1E
• Gene Name: MYO1E
• Related Disease:
  Steroid-resistant nephrotic syndrome
  Focal segmental glomerulosclerosis 6
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Metastatic prostate carcinoma
  Neoplasm
  Nephropathy
  Prostate cancer
  Prostate carcinoma
  Severe combined immunodeficiency
  Vascular disease
  Chronic obstructive pulmonary disease
  Focal segmental glomerulosclerosis
  Familial idiopathic steroid-resistant nephrotic syndrome
  Nephrotic syndrome, type 2
  Nephrotic syndrome
  X-linked hydrocephalus with stenosis of the aqueduct of Sylvius
• UniProt ID: MYO1E_HUMAN
• Pfam ID: PF00063 ; PF06017 ; PF00018
• Sequence:
  MGSKGVYQYHWQSHNVKHSGVDDMVLLSKITENSIVENLKKRYMDDYIFTYIGSVLISVN
  PFKQMPYFGEKEIEMYQGAAQYENPPHIYALADNMYRNMIIDRENQCVIISGESGAGKTV
  AAKYIMSYISRVSGGGTKVQHVKDIILQSNPLLEAFGNAKTVRNNNSSRFGKYFEIQFSP
  GGEPDGGKISNFLLEKSRVVMRNPGERSFHIFYQLIEGASAEQKHSLGITSMDYYYYLSL
  SGSYKVDDIDDRREFQETLHAMNVIGIFAEEQTLVLQIVAGILHLGNISFKEVGNYAAVE
  SEEFLAFPAYLLGINQDRLKEKLTSRQMDSKWGGKSESIHVTLNVEQACYTRDALAKALH
  ARVFDFLVDSINKAMEKDHEEYNIGVLDIYGFEIFQKNGFEQFCINFVNEKLQQIFIELT
  LKAEQEEYVQEGIRWTPIEYFNNKIVCDLIENKVNPPGIMSILDDVCATMHAVGEGADQT
  LLQKLQMQIGSHEHFNSWNQGFIIHHYAGKVSYDMDGFCERNRDVLFMDLIELMQSSELP
  FIKSLFPENLQADKKGRPTTAGSKIKKQANDLVSTLMKCTPHYIRCIKPNETKKPRDWEE
  SRVKHQVEYLGLKENIRVRRAGYAYRRIFQKFLQRYAILTKATWPSWQGEEKQGVLHLLQ
  SVNMDSDQFQLGRSKVFIKAPESLFLLEEMRERKYDGYARVIQKSWRKFVARKKYVQMRE
  EASDLLLNKKERRRNSINRNFIGDYIGMEEHPELQQFVGKREKIDFADTVTKYDRRFKGV
  KRDLLLTPKCLYLIGREKVKQGPDKGLVKEVLKRKIEIERILSVSLSTMQDDIFILHEQE
  YDSLLESVFKTEFLSLLAKRYEEKTQKQLPLKFSNTLELKLKKENWGPWSAGGSRQVQFH
  QGFGDLAVLKPSNKVLQVSIGPGLPKNSRPTRRNTTQNTGYSSGTQNANYPVRAAPPPPG
  YHQNGVIRNQYVPYPHAPGSQRSNQKSLYTSMARPPLPRQQSTSSDRVSQTPESLDFLKV
  PDQGAAGVRRQTTSRPPPAGGRPKPQPKPKPQVPQCKALYAYDAQDTDELSFNANDIIDI
  IKEDPSGWWTGRLRGKQGLFPNNYVTKI
• Function: Actin-based motor molecule with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails bind to membranous compartments, which are then moved relative to actin filaments. Binds to membranes containing anionic phospholipids via its tail domain. Involved in clathrin-mediated endocytosis and intracellular movement of clathrin-coated vesicles. Required for normal morphology of the glomerular basement membrane, normal development of foot processes by kidney podocytes and normal kidney function. In dendritic cells, may control the movement of class II-containing cytoplasmic vesicles along the actin cytoskeleton by connecting them with the actin network via ARL14EP and ARL14.
• Tissue Specificity: Expressed in the immune system. In the kidney, predominantly expressed in the glomerulus, including podocytes.
• KEGG Pathway:
  Motor proteins (hsa04814)
  Pathogenic Escherichia coli infection (hsa05130)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Steroid-resistant nephrotic syndrome	DISVEBC9	Definitive	Genetic Variation	[1]
Focal segmental glomerulosclerosis 6	DIST4PBC	Strong	Autosomal recessive	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[4]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Altered Expression	[7]
Vascular disease	DISVS67S	Strong	Biomarker	[8]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[9]
Focal segmental glomerulosclerosis	DISJNHH0	moderate	Genetic Variation	[10]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[11]
Nephrotic syndrome, type 2	DISIRFO1	Disputed	GermlineCausalMutation	[11]
Nephrotic syndrome	DISSPSC2	Limited	Genetic Variation	[6]
X-linked hydrocephalus with stenosis of the aqueduct of Sylvius	DIS6QXIR	Limited	Genetic Variation	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Unconventional myosin-Ie (MYO1E) affects the response to substance of Methotrexate.	[34]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Unconventional myosin-Ie (MYO1E).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Unconventional myosin-Ie (MYO1E).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Unconventional myosin-Ie (MYO1E).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Unconventional myosin-Ie (MYO1E).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Unconventional myosin-Ie (MYO1E).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Unconventional myosin-Ie (MYO1E).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Unconventional myosin-Ie (MYO1E).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Unconventional myosin-Ie (MYO1E).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Unconventional myosin-Ie (MYO1E).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Unconventional myosin-Ie (MYO1E).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Unconventional myosin-Ie (MYO1E).	[21]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Unconventional myosin-Ie (MYO1E).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Unconventional myosin-Ie (MYO1E).	[23]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of Unconventional myosin-Ie (MYO1E).	[23]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose decreases the expression of Unconventional myosin-Ie (MYO1E).	[23]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of Unconventional myosin-Ie (MYO1E).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Unconventional myosin-Ie (MYO1E).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Unconventional myosin-Ie (MYO1E).	[25]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Unconventional myosin-Ie (MYO1E).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Unconventional myosin-Ie (MYO1E).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Unconventional myosin-Ie (MYO1E).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Unconventional myosin-Ie (MYO1E).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Unconventional myosin-Ie (MYO1E).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Unconventional myosin-Ie (MYO1E).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Unconventional myosin-Ie (MYO1E).	[33]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Unconventional myosin-Ie (MYO1E).	[26]

References

• [1] Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.Kidney Int. 2011 Aug;80(4):389-96. doi: 10.1038/ki.2011.148. Epub 2011 Jun 22.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Genes associated with recurrence of hepatocellular carcinoma: integrated analysis by gene expression and methylation profiling.J Korean Med Sci. 2011 Nov;26(11):1428-38. doi: 10.3346/jkms.2011.26.11.1428. Epub 2011 Oct 27.
• [4] Selective expression of myosin IC Isoform A in mouse and human cell lines and mouse prostate cancer tissues.PLoS One. 2014 Sep 26;9(9):e108609. doi: 10.1371/journal.pone.0108609. eCollection 2014.
• [5] Myosin isoform expressed in metastatic prostate cancer stimulates cell invasion.Sci Rep. 2017 Aug 16;7(1):8476. doi: 10.1038/s41598-017-09158-5.
• [6] Promises and pitfalls of whole-exome sequencing exemplified by a nephrotic syndrome family.Mol Genet Genomics. 2020 Jan;295(1):135-142. doi: 10.1007/s00438-019-01609-0. Epub 2019 Sep 13.
• [7] Identification of Proteins Differentially Expressed by Adipose-derived Mesenchymal Stem Cells Isolated from Immunodeficient Mice.Int J Mol Sci. 2019 May 30;20(11):2672. doi: 10.3390/ijms20112672.
• [8] Exosomes from mesenchymal stem cells expressing miR-125b inhibit neointimal hyperplasia via myosin IE.J Cell Mol Med. 2019 Feb;23(2):1528-1540. doi: 10.1111/jcmm.14060. Epub 2018 Nov 28.
• [9] Whole exome sequencing identifies novel candidate genes that modify chronic obstructive pulmonary disease susceptibility.Hum Genomics. 2016 Jan 7;10:1. doi: 10.1186/s40246-015-0058-7.
• [10] Effects of FSGS-associated mutations on the stability and function of myosin-1 in fission yeast.Dis Model Mech. 2015 Aug 1;8(8):891-902. doi: 10.1242/dmm.020214. Epub 2015 Jun 18.
• [11] MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N Engl J Med. 2011 Jul 28;365(4):295-306. doi: 10.1056/NEJMoa1101273. Epub 2011 Jul 14.
• [12] Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease.Pediatr Nephrol. 2015 Sep;30(9):1459-65. doi: 10.1007/s00467-015-3067-9. Epub 2015 Mar 5.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] 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.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Identification of novel genes associated with the response to 5-FU treatment in gastric cancer cell lines using a cDNA microarray. Cancer Lett. 2004 Oct 8;214(1):19-33.
• [23] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [26] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [27] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] 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.
• [30] 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.
• [31] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [34] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.