Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCFV3ON)

• DOT Name: Dedicator of cytokinesis protein 1 (DOCK1)
• Synonyms: 180 kDa protein downstream of CRK; DOCK180
• Gene Name: DOCK1
• Related Disease:
  Acute myelogenous leukaemia
  Glioma
  Adult glioblastoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Chronic obstructive pulmonary disease
  Digestive system carcinoma
  Drug dependence
  Duchenne muscular dystrophy
  Epithelial ovarian cancer
  Gastric cancer
  Glioblastoma multiforme
  Malignant glioma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Polycystic ovarian syndrome
  Schizophrenia
  Stomach cancer
  Substance abuse
  Substance dependence
  Triple negative breast cancer
  Her2-receptor negative breast cancer
  HER2/NEU overexpressing breast cancer
• UniProt ID: DOCK1_HUMAN
• PDB ID: 3L4C
• Pfam ID: PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF16172 ; PF00018
• Sequence:
  MTRWVPTKREEKYGVAFYNYDARGADELSLQIGDTVHILETYEGWYRGYTLRKKSKKGIF
  PASYIHLKEAIVEGKGQHETVIPGDLPLIQEVTTTLREWSTIWRQLYVQDNREMFRSVRH
  MIYDLIEWRSQILSGTLPQDELKELKKKVTAKIDYGNRILDLDLVVRDEDGNILDPELTS
  TISLFRAHEIASKQVEERLQEEKSQKQNIDINRQAKFAATPSLALFVNLKNVVCKIGEDA
  EVLMSLYDPVESKFISENYLVRWSSSGLPKDIDRLHNLRAVFTDLGSKDLKREKISFVCQ
  IVRVGRMELRDNNTRKLTSGLRRPFGVAVMDVTDIINGKVDDEDKQHFIPFQPVAGENDF
  LQTVINKVIAAKEVNHKGQGLWVTLKLLPGDIHQIRKEFPHLVDRTTAVARKTGFPEIIM
  PGDVRNDIYVTLVQGDFDKGSKTTAKNVEVTVSVYDEDGKRLEHVIFPGAGDEAISEYKS
  VIYYQVKQPRWFETVKVAIPIEDVNRSHLRFTFRHRSSQDSKDKSEKIFALAFVKLMRYD
  GTTLRDGEHDLIVYKAEAKKLEDAATYLSLPSTKAELEEKGHSATGKSMQSLGSCTISKD
  SFQISTLVCSTKLTQNVDLLGLLKWRSNTSLLQQNLRQLMKVDGGEVVKFLQDTLDALFN
  IMMENSESETFDTLVFDALVFIIGLIADRKFQHFNPVLETYIKKHFSATLAYTKLTKVLK
  NYVDGAEKPGVNEQLYKAMKALESIFKFIVRSRILFNQLYENKGEADFVESLLQLFRSIN
  DMMSSMSDQTVRVKGAALKYLPTIVNDVKLVFDPKELSKMFTEFILNVPMGLLTIQKLYC
  LIEIVHSDLFTQHDCREILLPMMTDQLKYHLERQEDLEACCQLLSHILEVLYRKDVGPTQ
  RHVQIIMEKLLRTVNRTVISMGRDSELIGNFVACMTAILRQMEDYHYAHLIKTFGKMRTD
  VVDFLMETFIMFKNLIGKNVYPFDWVIMNMVQNKVFLRAINQYADMLNKKFLDQANFELQ
  LWNNYFHLAVAFLTQESLQLENFSSAKRAKILNKYGDMRRQIGFEIRDMWYNLGQHKIKF
  IPEMVGPILEMTLIPETELRKATIPIFFDMMQCEFHSTRSFQMFENEIITKLDHEVEGGR
  GDEQYKVLFDKILLEHCRKHKYLAKTGETFVKLVVRLMERLLDYRTIMHDENKENRMSCT
  VNVLNFYKEIEREEMYIRYLYKLCDLHKECDNYTEAAYTLLLHAKLLKWSEDVCVAHLTQ
  RDGYQATTQGQLKEQLYQEIIHYFDKGKMWEEAIALGKELAEQYENEMFDYEQLSELLKK
  QAQFYENIVKVIRPKPDYFAVGYYGQGFPTFLRGKVFIYRGKEYERREDFEARLLTQFPN
  AEKMKTTSPPGDDIKNSPGQYIQCFTVKPKLDLPPKFHRPVSEQIVSFYRVNEVQRFEYS
  RPIRKGEKNPDNEFANMWIERTIYTTAYKLPGILRWFEVKSVFMVEISPLENAIETMQLT
  NDKINSMVQQHLDDPSLPINPLSMLLNGIVDPAVMGGFANYEKAFFTDRYLQEHPEAHEK
  IEKLKDLIAWQIPFLAEGIRIHGDKVTEALRPFHERMEACFKQLKEKVEKEYGVRIMPSS
  LDDRRGSRPRSMVRSFTMPSSSRPLSVASVSSLSSDSTPSRPGSDGFALEPLLPKKMHSR
  SQDKLDKDDLEKEKKDKKKEKRNSKHQEIFEKEFKPTDISLQQSEAVILSETISPLRPQR
  PKSQVMNVIGSERRFSVSPSSPSSQQTPPPVTPRAKLSFSMQSSLELNGMTGADVADVPP
  PLPLKGSVADYGNLMENQDLLGSPTPPPPPPHQRHLPPPLPSKTPPPPPPKTTRKQASVD
  SGIVQ
• Function: Involved in cytoskeletal rearrangements required for phagocytosis of apoptotic cells and cell motility. Along with DOCK1, mediates CRK/CRKL regulation of epithelial and endothelial cell spreading and migration on type IV collagen. Functions as a guanine nucleotide exchange factor (GEF), which activates Rac Rho small GTPases by exchanging bound GDP for free GTP. Its GEF activity may be enhanced by ELMO1.
• Tissue Specificity: Highly expressed in placenta, lung, kidney, pancreas and ovary. Expressed at intermediate level in thymus, testes and colon.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Focal adhesion (hsa04510)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Regulation of actin cytoskeleton (hsa04810)
  Bacterial invasion of epithelial cells (hsa05100)
  Shigellosis (hsa05131)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  DCC mediated attractive signaling (R-HSA-418885)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[7]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[8]
Digestive system carcinoma	DISFC6MM	Strong	Genetic Variation	[8]
Drug dependence	DIS9IXRC	Strong	Biomarker	[9]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[11]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[12]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Malignant glioma	DISFXKOV	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[11]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[11]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[14]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[15]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[12]
Substance abuse	DIS327VW	Strong	Biomarker	[9]
Substance dependence	DISDRAAR	Strong	Biomarker	[9]
Triple negative breast cancer	DISAMG6N	moderate	Altered Expression	[4]
Her2-receptor negative breast cancer	DISS605N	Limited	Altered Expression	[16]
HER2/NEU overexpressing breast cancer	DISYKID5	Limited	Altered Expression	[16]

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 Dedicator of cytokinesis protein 1 (DOCK1).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Dedicator of cytokinesis protein 1 (DOCK1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Dedicator of cytokinesis protein 1 (DOCK1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dedicator of cytokinesis protein 1 (DOCK1).	[28]

8 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 Dedicator of cytokinesis protein 1 (DOCK1).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[22]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dedicator of cytokinesis protein 1 (DOCK1).	[26]

References

• [1] High expression of DOCK2 indicates good prognosis in acute myeloid leukemia.J Cancer. 2019 Oct 15;10(24):6088-6094. doi: 10.7150/jca.33244. eCollection 2019.
• [2] Dock1 promotes the mesenchymal transition of glioma and is modulated by MiR-31.Neuropathol Appl Neurobiol. 2017 Aug;43(5):419-432. doi: 10.1111/nan.12321. Epub 2016 Apr 28.
• [3] HGF-induced formation of the MET-AXL-ELMO2-DOCK180 complex promotes RAC1 activation, receptor clustering, and cancer cell migration and invasion.J Biol Chem. 2018 Oct 5;293(40):15397-15418. doi: 10.1074/jbc.RA118.003063. Epub 2018 Aug 14.
• [4] DOCK1 Regulates Growth and Motility through the RRP1B-Claudin-1 Pathway in Claudin-Low Breast Cancer Cells.Cancers (Basel). 2019 Nov 8;11(11):1762. doi: 10.3390/cancers11111762.
• [5] Circular RNA DOCK1 promotes bladder carcinoma progression via modulating circDOCK1/hsa-miR-132-3p/Sox5 signalling pathway.Cell Prolif. 2019 Jul;52(4):e12614. doi: 10.1111/cpr.12614. Epub 2019 Apr 14.
• [6] MiR-486-5p inhibits IL-22-induced epithelial-mesenchymal transition of breast cancer cell by repressing Dock1.J Cancer. 2019 Aug 19;10(19):4695-4706. doi: 10.7150/jca.30596. eCollection 2019.
• [7] Identification of critical regions for clinical features of distal 10q deletion syndrome.Clin Genet. 2009 Jul;76(1):54-62. doi: 10.1111/j.1399-0004.2008.01115.x. Epub 2009 Jun 22.
• [8] Body mass index change in gastrointestinal cancer and chronic obstructive pulmonary disease is associated with Dedicator of Cytokinesis 1.J Cachexia Sarcopenia Muscle. 2017 Jun;8(3):428-436. doi: 10.1002/jcsm.12171. Epub 2017 Jan 2.
• [9] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [10] Long-range genomic regulators of THBS1 and LTBP4 modify disease severity in duchenne muscular dystrophy.Ann Neurol. 2018 Aug;84(2):234-245. doi: 10.1002/ana.25283. Epub 2018 Aug 25.
• [11] Elmo1 helps dock180 to regulate Rac1 activity and cell migration of ovarian cancer.Int J Gynecol Cancer. 2014 Jun;24(5):844-50. doi: 10.1097/IGC.0000000000000137.
• [12] Oncogenic CagA promotes gastric cancer risk via activating ERK signaling pathways: a nested case-control study.PLoS One. 2011;6(6):e21155. doi: 10.1371/journal.pone.0021155. Epub 2011 Jun 16.
• [13] ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion.Cancer Res. 2007 Aug 1;67(15):7203-11. doi: 10.1158/0008-5472.CAN-07-0473.
• [14] RHOG-DOCK1-RAC1 Signaling Axis Is Perturbed in DHEA-Induced Polycystic Ovary in Rat Model.Reprod Sci. 2017 May;24(5):738-752. doi: 10.1177/1933719116669057. Epub 2016 Sep 22.
• [15] Whole-genome sequencing of monozygotic twins discordant for schizophrenia indicates multiple genetic risk factors for schizophrenia.J Genet Genomics. 2017 Jun 20;44(6):295-306. doi: 10.1016/j.jgg.2017.05.005. Epub 2017 Jun 8.
• [16] Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis.Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7434-9. doi: 10.1073/pnas.1213050110. Epub 2013 Apr 16.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [22] 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.
• [23] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [24] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [25] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [26] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [27] 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.
• [28] 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.