Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1TZEJK)

• DOT Name: Myosin-14 (MYH14)
• Synonyms: Myosin heavy chain 14; Myosin heavy chain, non-muscle IIc; Non-muscle myosin heavy chain IIc; NMHC II-C
• Gene Name: MYH14
• Related Disease:
  Autosomal dominant nonsyndromic hearing loss 4A
  Adult lymphoma
  Advanced cancer
  Bardet-Biedl syndrome 4
  Cardiac failure
  Cardiomyopathy
  Clubfoot
  Congenital myopathy 7A, myosin storage, autosomal dominant
  Congestive heart failure
  Deafness
  Hereditary nonpolyposis colon cancer
  Isolated cleft lip
  Lung adenocarcinoma
  Lymphoma
  Pediatric lymphoma
  Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
  Prostate cancer
  Prostate neoplasm
  Vascular disease
  Chronic kidney disease
  Hypertrophic cardiomyopathy
  Nonsyndromic genetic hearing loss
  Pancreatic cancer
  Stroke
  Autosomal dominant nonsyndromic hearing loss
  Dilated cardiomyopathy
  Neoplasm
  Myotonic dystrophy type 1
• UniProt ID: MYH14_HUMAN
• PDB ID: 5I4E; 5JLH
• Pfam ID: PF00063 ; PF02736 ; PF01576
• Sequence:
  MAAVTMSVPGRKAPPRPGPVPEAAQPFLFTPRGPSAGGGPGSGTSPQVEWTARRLVWVPS
  ELHGFEAAALRDEGEEEAEVELAESGRRLRLPRDQIQRMNPPKFSKAEDMAELTCLNEAS
  VLHNLRERYYSGLIYTYSGLFCVVINPYKQLPIYTEAIVEMYRGKKRHEVPPHVYAVTEG
  AYRSMLQDREDQSILCTGESGAGKTENTKKVIQYLAHVASSPKGRKEPGVPGELERQLLQ
  ANPILEAFGNAKTVKNDNSSRFGKFIRINFDVAGYIVGANIETYLLEKSRAIRQAKDECS
  FHIFYQLLGGAGEQLKADLLLEPCSHYRFLTNGPSSSPGQERELFQETLESLRVLGFSHE
  EIISMLRMVSAVLQFGNIALKRERNTDQATMPDNTAAQKLCRLLGLGVTDFSRALLTPRI
  KVGRDYVQKAQTKEQADFALEALAKATYERLFRWLVLRLNRALDRSPRQGASFLGILDIA
  GFEIFQLNSFEQLCINYTNEKLQQLFNHTMFVLEQEEYQREGIPWTFLDFGLDLQPCIDL
  IERPANPPGLLALLDEECWFPKATDKSFVEKVAQEQGGHPKFQRPRHLRDQADFSVLHYA
  GKVDYKANEWLMKNMDPLNDNVAALLHQSTDRLTAEIWKDVEGIVGLEQVSSLGDGPPGG
  RPRRGMFRTVGQLYKESLSRLMATLSNTNPSFVRCIVPNHEKRAGKLEPRLVLDQLRCNG
  VLEGIRICRQGFPNRILFQEFRQRYEILTPNAIPKGFMDGKQACEKMIQALELDPNLYRV
  GQSKIFFRAGVLAQLEEERDLKVTDIIVSFQAAARGYLARRAFQKRQQQQSALRVMQRNC
  AAYLKLRHWQWWRLFTKVKPLLQVTRQDEVLQARAQELQKVQELQQQSAREVGELQGRVA
  QLEEERARLAEQLRAEAELCAEAEETRGRLAARKQELELVVSELEARVGEEEECSRQMQT
  EKKRLQQHIQELEAHLEAEEGARQKLQLEKVTTEAKMKKFEEDLLLLEDQNSKLSKERKL
  LEDRLAEFSSQAAEEEEKVKSLNKLRLKYEATIADMEDRLRKEEKGRQELEKLKRRLDGE
  SSELQEQMVEQQQRAEELRAQLGRKEEELQAALARAEDEGGARAQLLKSLREAQAALAEA
  QEDLESERVARTKAEKQRRDLGEELEALRGELEDTLDSTNAQQELRSKREQEVTELKKTL
  EEETRIHEAAVQELRQRHGQALGELAEQLEQARRGKGAWEKTRLALEAEVSELRAELSSL
  QTARQEGEQRRRRLELQLQEVQGRAGDGERARAEAAEKLQRAQAELENVSGALNEAESKT
  IRLSKELSSTEAQLHDAQELLQEETRAKLALGSRVRAMEAEAAGLREQLEEEAAARERAG
  RELQTAQAQLSEWRRRQEEEAGALEAGEEARRRAAREAEALTQRLAEKTETVDRLERGRR
  RLQQELDDATMDLEQQRQLVSTLEKKQRKFDQLLAEEKAAVLRAVEERERAEAEGREREA
  RALSLTRALEEEQEAREELERQNRALRAELEALLSSKDDVGKSVHELERACRVAEQAAND
  LRAQVTELEDELTAAEDAKLRLEVTVQALKTQHERDLQGRDEAGEERRRQLAKQLRDAEV
  ERDEERKQRTLAVAARKKLEGELEELKAQMASAGQGKEEAVKQLRKMQAQMKELWREVEE
  TRTSREEIFSQNRESEKRLKGLEAEVLRLQEELAASDRARRQAQQDRDEMADEVANGNLS
  KAAILEEKRQLEGRLGQLEEELEEEQSNSELLNDRYRKLLLQVESLTTELSAERSFSAKA
  ESGRQQLERQIQELRGRLGEEDAGARARHKMTIAALESKLAQAEEQLEQETRERILSGKL
  VRRAEKRLKEVVLQVEEERRVADQLRDQLEKGNLRVKQLKRQLEEAEEEASRAQAGRRRL
  QRELEDVTESAESMNREVTTLRNRLRRGPLTFTTRTVRQVFRLEEGVASDEEAEEAQPGS
  GPSPEPEGSPPAHPQ
• Function: Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
• Tissue Specificity: High levels of expression are found in brain (highest in corpus callosum), heart, kidney, liver, lung, small intestine, colon and skeletal muscle. Expression is low in organs composed mainly of smooth muscle, such as aorta, uterus and urinary bladder. No detectable expression is found in thymus, spleen, placenta and lymphocytes.
• KEGG Pathway:
  Vascular smooth muscle contraction (hsa04270)
  Tight junction (hsa04530)
  Regulation of actin cytoskeleton (hsa04810)
  Motor proteins (hsa04814)
  Cytoskeleton in muscle cells (hsa04820)
  Pathogenic Escherichia coli infection (hsa05130)
• Reactome Pathway:
  Sema4D induced cell migration and growth-cone collapse (R-HSA-416572)
  RHO GTPases activate PKNs (R-HSA-5625740)
  RHO GTPases activate CIT (R-HSA-5625900)
  RHO GTPases Activate ROCKs (R-HSA-5627117)
  RHO GTPases activate PAKs (R-HSA-5627123)
  EPHA-mediated growth cone collapse (R-HSA-3928663)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nonsyndromic hearing loss 4A	DISBK1WH	Definitive	Autosomal dominant	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bardet-Biedl syndrome 4	DISTSZC7	Strong	Genetic Variation	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[5]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[6]
Clubfoot	DISLXT4S	Strong	Genetic Variation	[7]
Congenital myopathy 7A, myosin storage, autosomal dominant	DISUV37B	Strong	Altered Expression	[8]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[5]
Deafness	DISKCLH4	Strong	Genetic Variation	[9]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Genetic Variation	[10]
Isolated cleft lip	DIS2O2JV	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[12]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome	DISD2ZGX	Strong	Autosomal dominant	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[14]
Vascular disease	DISVS67S	Strong	Altered Expression	[15]
Chronic kidney disease	DISW82R7	moderate	Genetic Variation	[16]
Hypertrophic cardiomyopathy	DISQG2AI	moderate	Genetic Variation	[6]
Nonsyndromic genetic hearing loss	DISZX61P	Moderate	Autosomal dominant	[17]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[18]
Stroke	DISX6UHX	moderate	Biomarker	[19]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[20]
Dilated cardiomyopathy	DISX608J	Disputed	Genetic Variation	[21]
Neoplasm	DISZKGEW	Disputed	Biomarker	[22]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Myosin-14 (MYH14).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Myosin-14 (MYH14).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Myosin-14 (MYH14).	[26]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Myosin-14 (MYH14).	[27]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Myosin-14 (MYH14).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Myosin-14 (MYH14).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Myosin-14 (MYH14).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Myosin-14 (MYH14).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Myosin-14 (MYH14).	[30]

References

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• [2] miR-155 regulates HGAL expression and increases lymphoma cell motility.Blood. 2012 Jan 12;119(2):513-20. doi: 10.1182/blood-2011-08-370536. Epub 2011 Nov 16.
• [3] Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats.PeerJ. 2017 Dec 13;5:e4109. doi: 10.7717/peerj.4109. eCollection 2017.
• [4] The cloning and developmental expression of unconventional myosin IXA (MYO9A) a gene in the Bardet-Biedl syndrome (BBS4) region at chromosome 15q22-q23.Genomics. 1999 Jul 15;59(2):150-60. doi: 10.1006/geno.1999.5867.
• [5] Losartan decreases p42/44 MAPK signaling and preserves LZ+ MYPT1 expression.PLoS One. 2009;4(4):e5144. doi: 10.1371/journal.pone.0005144. Epub 2009 Apr 9.
• [6] Modulation of cardiac performance by motor protein gene transfer.Ann N Y Acad Sci. 2008 Mar;1123:96-104. doi: 10.1196/annals.1420.011.
• [7] Evaluation of embryonic and perinatal myosin gene mutations and the etiology of congenital idiopathic clubfoot.J Pediatr Orthop. 2010 Apr-May;30(3):231-4. doi: 10.1097/BPO.0b013e3181d35e3f.
• [8] Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells.PLoS One. 2017 Jan 26;12(1):e0170613. doi: 10.1371/journal.pone.0170613. eCollection 2017.
• [9] Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family.Muscle Nerve. 2017 Aug;56(2):341-345. doi: 10.1002/mus.25491. Epub 2017 Feb 20.
• [10] Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome.Br J Cancer. 2008 Nov 18;99(10):1726-8. doi: 10.1038/sj.bjc.6604737. Epub 2008 Oct 21.
• [11] Investigation of MYH14 as a candidate gene in cleft lip with or without cleft palate.Eur J Oral Sci. 2008 Jun;116(3):287-90. doi: 10.1111/j.1600-0722.2008.00534.x.
• [12] Systematic identification of cancer-related long noncoding RNAs and aberrant alternative splicing of quintuple-negative lung adenocarcinoma through RNA-Seq.Lung Cancer. 2017 Jul;109:21-27. doi: 10.1016/j.lungcan.2017.04.009. Epub 2017 Apr 21.
• [13] A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss is linked to an autosomal dominant mutation in MYH14. Hum Mutat. 2011 Jun;32(6):669-77. doi: 10.1002/humu.21488. Epub 2011 Apr 7.
• [14] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [15] Myosin gene expression and cell phenotypes in vascular smooth muscle during development, in experimental models, and in vascular disease.Arterioscler Thromb Vasc Biol. 1997 Jul;17(7):1210-5. doi: 10.1161/01.atv.17.7.1210.
• [16] Polymorphisms in the non-muscle myosin heavy chain gene (MYH9) are associated with lower glomerular filtration rate in mixed ancestry diabetic subjects from South Africa.PLoS One. 2012;7(12):e52529. doi: 10.1371/journal.pone.0052529. Epub 2012 Dec 20.
• [17] 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.
• [18] Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14.Cancer Res. 2019 Sep 15;79(18):4665-4678. doi: 10.1158/0008-5472.CAN-18-3131. Epub 2019 Jul 29.
• [19] Multidimensional structure-function relationships in human -cardiac myosin from population-scale genetic variation.Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6701-6. doi: 10.1073/pnas.1606950113. Epub 2016 May 31.
• [20] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [21] Converter domain mutations in myosin alter structural kinetics and motor function.J Biol Chem. 2019 Feb 1;294(5):1554-1567. doi: 10.1074/jbc.RA118.006128. Epub 2018 Dec 5.
• [22] A specific isoform of nonmuscle myosin II-C is required for cytokinesis in a tumor cell line.J Biol Chem. 2006 Aug 25;281(34):24662-70. doi: 10.1074/jbc.M604606200. Epub 2006 Jun 21.
• [23] Aberrant splicing and expression of the non muscle myosin heavy-chain gene MYH14 in DM1 muscle tissues.Neurobiol Dis. 2012 Jan;45(1):264-71. doi: 10.1016/j.nbd.2011.08.010. Epub 2011 Aug 18.
• [24] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [25] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [26] 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.
• [27] Nucleophosmin in the pathogenesis of arsenic-related bladder carcinogenesis revealed by quantitative proteomics. Toxicol Appl Pharmacol. 2010 Jan 15;242(2):126-35. doi: 10.1016/j.taap.2009.09.016. Epub 2009 Oct 7.
• [28] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [29] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [30] 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.
• [31] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [32] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.