Details of Drug Off-Target (DOT)

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

DOT Name Dedicator of cytokinesis protein 6 (DOCK6)
Gene Name DOCK6
Related Disease
Adams-Oliver syndrome ( )
Acute myelogenous leukaemia ( )
Adams-Oliver syndrome 1 ( )
Adams-Oliver syndrome 2 ( )
Aplasia cutis congenita ( )
Corpus callosum, agenesis of ( )
Vascular disease ( )
Intellectual disability ( )
Gastric cancer ( )
Stomach cancer ( )
UniProt ID
DOCK6_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF11878
Sequence
MAASERRAFAHKINRTVAAEVRKQVSRERSGSPHSSRRCSSSLGVPLTEVVEPLDFEDVL
LSRPPDAEPGPLRDLVEFPADDLELLLQPRECRTTEPGIPKDEKLDAQVRAAVEMYIEDW
VIVHRRYQYLSAAYSPVTTDTQRERQKGLPRQVFEQDASGDERSGPEDSNDSRRGSGSPE
DTPRSSGASSIFDLRNLAADSLLPSLLERAAPEDVDRRNETLRRQHRPPALLTLYPAPDE
DEAVERCSRPEPPREHFGQRILVKCLSLKFEIEIEPIFGILALYDVREKKKISENFYFDL
NSDSMKGLLRAHGTHPAISTLARSAIFSVTYPSPDIFLVIKLEKVLQQGDISECCEPYMV
LKEVDTAKNKEKLEKLRLAAEQFCTRLGRYRMPFAWTAVHLANIVSSAGQLDRDSDSEGE
RRPAWTDRRRRGPQDRASSGDDACSFSGFRPATLTVTNFFKQEAERLSDEDLFKFLADMR
RPSSLLRRLRPVTAQLKIDISPAPENPHFCLSPELLHIKPYPDPRGRPTKEILEFPAREV
YAPHTSYRNLLYVYPHSLNFSSRQGSVRNLAVRVQYMTGEDPSQALPVIFGKSSCSEFTR
EAFTPVVYHNKSPEFYEEFKLHLPACVTENHHLLFTFYHVSCQPRPGTALETPVGFTWIP
LLQHGRLRTGPFCLPVSVDQPPPSYSVLTPDVALPGMRWVDGHKGVFSVELTAVSSVHPQ
DPYLDKFFTLVHVLEEGAFPFRLKDTVLSEGNVEQELRASLAALRLASPEPLVAFSHHVL
DKLVRLVIRPPIISGQIVNLGRGAFEAMAHVVSLVHRSLEAAQDARGHCPQLAAYVHYAF
RLPGTEPSLPDGAPPVTVQAATLARGSGRPASLYLARSKSISSSNPDLAVAPGSVDDEVS
RILASKLLHEELALQWVVSSSAVREAILQHAWFFFQLMVKSMALHLLLGQRLDTPRKLRF
PGRFLDDITALVGSVGLEVITRVHKDVELAEHLNASLAFFLSDLLSLVDRGFVFSLVRAH
YKQVATRLQSSPNPAALLTLRMEFTRILCSHEHYVTLNLPCCPLSPPASPSPSVSSTTSQ
SSTFSSQAPDPKVTSMFELSGPFRQQHFLAGLLLTELALALEPEAEGAFLLHKKAISAVH
SLLCGHDTDPRYAEATVKARVAELYLPLLSIARDTLPRLHDFAEGPGQRSRLASMLDSDT
EGEGDIAGTINPSVAMAIAGGPLAPGSRASISQGPPTASRAGCALSAESSRTLLACVLWV
LKNTEPALLQRWATDLTLPQLGRLLDLLYLCLAAFEYKGKKAFERINSLTFKKSLDMKAR
LEEAILGTIGARQEMVRRSRERSPFGNPENVRWRKSVTHWKQTSDRVDKTKDEMEHEALV
EGNLATEASLVVLDTLEIIVQTVMLSEARESVLGAVLKVVLYSLGSAQSALFLQHGLATQ
RALVSKFPELLFEEDTELCADLCLRLLRHCGSRISTIRTHASASLYLLMRQNFEIGHNFA
RVKMQVTMSLSSLVGTTQNFSEEHLRRSLKTILTYAEEDMGLRDSTFAEQVQDLMFNLHM
ILTDTVKMKEHQEDPEMLIDLMYRIARGYQGSPDLRLTWLQNMAGKHAELGNHAEAAQCM
VHAAALVAEYLALLEDHRHLPVGCVSFQNISSNVLEESAISDDILSPDEEGFCSGKHFTE
LGLVGLLEQAAGYFTMGGLYEAVNEVYKNLIPILEAHRDYKKLAAVHGKLQEAFTKIMHQ
SSGWERVFGTYFRVGFYGAHFGDLDEQEFVYKEPSITKLAEISHRLEEFYTERFGDDVVE
IIKDSNPVDKSKLDSQKAYIQITYVEPYFDTYELKDRVTYFDRNYGLRTFLFCTPFTPDG
RAHGELPEQHKRKTLLSTDHAFPYIKTRIRVCHREETVLTPVEVAIEDMQKKTRELAFAT
EQDPPDAKMLQMVLQGSVGPTVNQGPLEVAQVFLAEIPEDPKLFRHHNKLRLCFKDFCKK
CEDALRKNKALIGPDQKEYHRELERNYCRLREALQPLLTQRLPQLMAPTPPGLRNSLNRA
SFRKADL
Function Acts as a guanine nucleotide exchange factor (GEF) for CDC42 and RAC1 small GTPases. Through its activation of CDC42 and RAC1, may regulate neurite outgrowth.
Tissue Specificity Widely expressed. Expressed at low level in spleen, cerebellum, hippocampus and in substantia nigra.
Reactome Pathway
RAC1 GTPase cycle (R-HSA-9013149 )
Factors involved in megakaryocyte development and platelet production (R-HSA-983231 )
CDC42 GTPase cycle (R-HSA-9013148 )

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adams-Oliver syndrome DISQO525 Definitive Autosomal recessive [1]
Acute myelogenous leukaemia DISCSPTN Strong Genetic Variation [2]
Adams-Oliver syndrome 1 DISC3I62 Strong Genetic Variation [3]
Adams-Oliver syndrome 2 DISYM7SK Strong Autosomal recessive [4]
Aplasia cutis congenita DISMDAYM Strong Genetic Variation [5]
Corpus callosum, agenesis of DISO9P40 Strong Genetic Variation [5]
Vascular disease DISVS67S Strong Genetic Variation [6]
Intellectual disability DISMBNXP Disputed Genetic Variation [7]
Gastric cancer DISXGOUK Limited Altered Expression [8]
Stomach cancer DISKIJSX Limited Altered Expression [8]
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⏷ Show the Full List of 10 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate affects the expression of Dedicator of cytokinesis protein 6 (DOCK6). [9]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [10]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [11]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [12]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [13]
Temozolomide DMKECZD Approved Temozolomide increases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [14]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [15]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [16]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [18]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Dedicator of cytokinesis protein 6 (DOCK6). [20]
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⏷ Show the Full List of 10 Drug(s)
2 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 affects the methylation of Dedicator of cytokinesis protein 6 (DOCK6). [17]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Dedicator of cytokinesis protein 6 (DOCK6). [19]
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References

1 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.
2 Tracing the development of acute myeloid leukemia in CBL syndrome.Blood. 2014 Mar 20;123(12):1883-6. doi: 10.1182/blood-2013-10-533844. Epub 2014 Feb 3.
3 Adams-Oliver syndrome caused by mutations of the EOGT gene.Am J Med Genet A. 2019 Nov;179(11):2246-2251. doi: 10.1002/ajmg.a.61313. Epub 2019 Jul 31.
4 Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. Am J Hum Genet. 2011 Aug 12;89(2):328-33. doi: 10.1016/j.ajhg.2011.07.009. Epub 2011 Aug 4.
5 Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.Hum Mutat. 2018 Sep;39(9):1246-1261. doi: 10.1002/humu.23567. Epub 2018 Jul 4.
6 Diffuse angiopathy in Adams-Oliver syndrome associated with truncating DOCK6 mutations.Am J Med Genet A. 2014 Oct;164A(10):2656-62. doi: 10.1002/ajmg.a.36685. Epub 2014 Aug 4.
7 DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.Hum Mutat. 2015 Jun;36(6):593-8. doi: 10.1002/humu.22795. Epub 2015 Apr 21.
8 miR-148b-3p inhibits gastric cancer metastasis by inhibiting the Dock6/Rac1/Cdc42 axis.J Exp Clin Cancer Res. 2018 Mar 27;37(1):71. doi: 10.1186/s13046-018-0729-z.
9 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
10 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
11 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.
12 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.
13 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.
14 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
15 Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
16 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
17 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.
18 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.
19 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.
20 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.