Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF3YS2W)

• DOT Name: Dedicator of cytokinesis protein 3 (DOCK3)
• Synonyms: Modifier of cell adhesion; Presenilin-binding protein; PBP
• Gene Name: DOCK3
• Related Disease:
  Attention deficit hyperactivity disorder
  Acute intermittent hepatic porphyria
  Acute otitis media
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Bullous pemphigoid
  Cerebellar ataxia
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Familial Alzheimer disease
  Influenza
  Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia
  Non-small-cell lung cancer
  Polycystic kidney disease 1
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Varicose veins
  Acute myelogenous leukaemia
  Melanoma
  Neoplasm
  Syndromic intellectual disability
  Glaucoma/ocular hypertension
  Movement disorder
  Neurodevelopmental disorder
  Parkinson disease
  Streptococcal pneumonia
  Type-1/2 diabetes
• UniProt ID: DOCK3_HUMAN
• Pfam ID: PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF16172 ; PF07653
• Sequence:
  MWTPTEEEKYGVVICSFRGSVPQGLVLEIGETVQILEKCEGWYRGVSTKKPNVKGIFPAN
  YIHLKKAIVSNRGQYETVVPLEDSIVTEVTATLQEWASLWKQLYVKHKVDLFYKLRHVMN
  ELIDLRRQLLSGHLTQDQVREVKRHITVRLDWGNEHLGLDLVPRKDFEVVDSDQISVSDL
  YKMHLSSRQSVQQSTSQVDTMRPRHGETCRMPVPHHFFLSLKSFTYNTIGEDTDVFFSLY
  DMREGKQISERFLVRLNKNGGPRNPEKIERMCALFTDLSSKDMKRDLYIVAHVIRIGRML
  LNDSKKGPPHLHYRRPYGCAVLSILDVLQSLTEVKEEKDFVLKVYTCNNESEWSQIHENI
  IRKSSAKYSAPSASHGLIISLQLLRGDMEQIRRENPMIFNRGLAITRKLGFPDVIMPGDI
  RNDLYLTLEKGDFERGGKSVQKNIEVTMYVLYADGEILKDCISLGSGEPNRSSYHSFVLY
  HSNSPRWGEIIKLPIPIDRFRGSHLRFEFRHCSTKDKGEKKLFGFAFSTLMRDDGTTLSD
  DIHELYVYKCDENSTFNNHALYLGLPCCKEDYNGCPNIPSSLIFQRSTKESFFISTQLSS
  TKLTQNVDLLALLKWKAFPDRIMDVLGRLRHVSGEEIVKFLQDILDTLFVILDDNTEKYG
  LLVFQSLVFIINLLRDIKYFHFRPVMDTYIQKHFAGALAYKELIRCLKWYMDCSAELIRQ
  DHIQEAMRALEYLFKFIVQSRILYSRATCGMEEEQFRSSIQELFQSIRFVLSLDSRNSET
  LLFTQAALLNSFPTIFDELLQMFTVQEVAEFVRGTLGSMPSTVHIGQSMDVVKLQSIART
  VDSRLFSFSESRRILLPVVLHHIHLHLRQQKELLICSGILGSIFSIVKTSSLEADVMEEV
  EMMVESLLDVLLQTLLTIMSKSHAQEAVRGQRCPQCTAEITGEYVSCLLSLLRQMCDTHF
  QHLLDNFQSKDELKEFLLKIFCVFRNLMKMSVFPRDWMVMRLLTSNIIVTTVQYLSSALH
  KNFTETDFDFKVWNSYFSLAVLFINQPSLQLEIITSAKRKKILDKYGDMRVMMAYELFSM
  WQNLGEHKIHFIPGMIGPFLGVTLVPQPEVRNIMIPIFHDMMDWEQRKNGNFKQVEAELI
  DKLDSMVSEGKGDESYRELFSLLTQLFGPYPSLLEKVEQETWRETGISFVTSVTRLMERL
  LDYRDCMKGEETENKKIGCTVNLMNFYKSEINKEEMYIRYIHKLCDMHLQAENYTEAAFT
  LLLYCELLQWEDRPLREFLHYPSQTEWQRKEGLCRKIIHYFNKGKSWEFGIPLCRELACQ
  YESLYDYQSLSWIRKMEASYYDNIMEQQRLEPEFFRVGFYGRKFPFFLRNKEYVCRGHDY
  ERLEAFQQRMLSEFPQAVAMQHPNHPDDAILQCDAQYLQIYAVTPIPDYVDVLQMDRVPD
  RVKSFYRVNNVRKFRYDRPFHKGPKDKENEFKSLWIERTTLTLTHSLPGISRWFEVERRE
  LVEVSPLENAIQVVENKNQELRSLISQYQHKQVHGNINLLSMCLNGVIDAAVNGGIARYQ
  EAFFDKDYINKHPGDAEKITQLKELMQEQVHVLGVGLAVHEKFVHPEMRPLHKKLIDQFQ
  MMRASLYHEFPGLDKLSPACSGTSTPRGNVLASHSPMSPESIKMTHRHSPMNLMGTGRHS
  SSSLSSHASSEAGNMVMLGDGSMGDAPEDLYHHMQLAYPNPRYQGSVTNVSVLSSSQASP
  SSSSLSSTHSAPSQMITSAPSSARGSPSLPDKYRHAREMMLLLPTYRDRPSSAMYPAAIL
  ENGQPPNFQRALFQQVVGACKPCSDPNLSVAEKGHYSLHFDAFHHPLGDTPPALPARTLR
  KSPLHPIPASPTSPQSGLDGSNSTLSGSASSGVSSLSESNFGHSSEAPPRTDTMDSMPSQ
  AWNADEDLEPPYLPVHYSLSESAVLDSIKAQPCRSHSAPGCVIPQDPMDPPALPPKPYHP
  RLPALEHDEGVLLREETERPRGLHRKAPLPPGSAKEEQARMAWEHGRGEQ
• Function: Potential guanine nucleotide exchange factor (GEF). GEF proteins activate some small GTPases by exchanging bound GDP for free GTP. Its interaction with presenilin proteins as well as its ability to stimulate Tau/MAPT phosphorylation suggest that it may be involved in Alzheimer disease. Ectopic expression in nerve cells decreases the secretion of amyloid-beta APBA1 protein and lowers the rate of cell-substratum adhesion, suggesting that it may affect the function of some small GTPase involved in the regulation of actin cytoskeleton or cell adhesion receptors.
• Tissue Specificity: In normal brains, it is localized in the neuropil, and occasionally in the pyramidal cells, while in Alzheimer disease brains, it is associated with neurofibrillary tangles.
• Reactome Pathway:
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  NTRK2 activates RAC1 (R-HSA-9032759)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Attention deficit hyperactivity disorder	DISL8MX9	Definitive	Biomarker	[1]
Acute intermittent hepatic porphyria	DIS80J7E	Strong	Biomarker	[2]
Acute otitis media	DISL8D8G	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Bullous pemphigoid	DISOJLKV	Strong	Biomarker	[6]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Genetic Variation	[8]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[8]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[8]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[8]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[8]
Familial Alzheimer disease	DISE75U4	Strong	Altered Expression	[9]
Influenza	DIS3PNU3	Strong	Genetic Variation	[10]
Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia	DIS0PBFD	Strong	Autosomal recessive	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[12]
Polycystic kidney disease 1	DIS9FB3R	Strong	Genetic Variation	[13]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[14]
Varicose veins	DISIMBN2	Strong	Biomarker	[15]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[16]
Melanoma	DIS1RRCY	moderate	Biomarker	[17]
Neoplasm	DISZKGEW	moderate	Biomarker	[17]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[7]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[18]
Movement disorder	DISOJJ2D	Limited	Genetic Variation	[19]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[19]
Parkinson disease	DISQVHKL	Limited	Biomarker	[20]
Streptococcal pneumonia	DIS2EKMJ	Limited	Genetic Variation	[21]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[26]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[29]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Dedicator of cytokinesis protein 3 (DOCK3).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dedicator of cytokinesis protein 3 (DOCK3).	[30]

References

• [1] Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype.J Med Genet. 2003 Oct;40(10):733-40. doi: 10.1136/jmg.40.10.733.
• [2] No evidence to support a role for Helicobacter pylori infection and plasminogen binding protein in autoimmune pancreatitis and IgG4-related disease in a UK cohort.Pancreatology. 2017 May-Jun;17(3):395-402. doi: 10.1016/j.pan.2017.04.002. Epub 2017 Apr 5.
• [3] Nasopharyngeal carriage of drug-resistant Streptococcus pneumoniae in children with acute otitis media evaluated by polymerase chain reaction-based genotyping of penicillin-binding proteins.Acta Otolaryngol. 2002 Jan;122(1):72-7. doi: 10.1080/00016480252775779.
• [4] CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3--catenin-WAVE2 signaling.Oncotarget. 2016 Feb 2;7(5):5613-29. doi: 10.18632/oncotarget.6723.
• [5] Amplification and overexpression of peroxisome proliferator-activated receptor binding protein (PBP/PPARBP) gene in breast cancer.Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10848-53. doi: 10.1073/pnas.96.19.10848.
• [6] Non-bullous lesions as the first manifestation of bullous pemphigoid: A retrospective analysis of 181 cases.J Dermatol. 2017 Jul;44(7):742-746. doi: 10.1111/1346-8138.13782. Epub 2017 Mar 3.
• [7] Variants in DOCK3 cause developmental delay and hypotonia. Eur J Hum Genet. 2019 Aug;27(8):1225-1234. doi: 10.1038/s41431-019-0397-2. Epub 2019 Apr 11.
• [8] Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.Oncotarget. 2017 Oct 9;8(58):98623-98634. doi: 10.18632/oncotarget.21697. eCollection 2017 Nov 17.
• [9] MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid precursor protein and presenilins.Biochem J. 2012 Mar 1;442(2):413-22. doi: 10.1042/BJ20100993.
• [10] Molecular diagnosis and characterization of a culture-negative mycotic aneurysm due to ST54 Haemophilus influenzae type b with PBP 3 alterations.J Infect Chemother. 2018 Jul;24(7):570-572. doi: 10.1016/j.jiac.2017.12.013. Epub 2018 Jan 17.
• [11] Biallelic loss-of-function variants in DOCK3 cause muscle hypotonia, ataxia, and intellectual disability. Clin Genet. 2017 Oct;92(4):430-433. doi: 10.1111/cge.12995. Epub 2017 Mar 30.
• [12] Inhibition of RAC1-GEF DOCK3 by miR-512-3p contributes to suppression of metastasis in non-small cell lung cancer.Int J Biochem Cell Biol. 2015 Apr;61:103-14. doi: 10.1016/j.biocel.2015.02.005. Epub 2015 Feb 14.
• [13] The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium.Cell. 1994 Jun 17;77(6):881-94. doi: 10.1016/0092-8674(94)90137-6.
• [14] Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarray of 25 344 genes.Endocr Relat Cancer. 2004 Dec;11(4):843-54. doi: 10.1677/erc.1.00818.
• [15] Cost-Effectiveness of Current and Emerging Treatments of Varicose Veins.Value Health. 2018 Aug;21(8):911-920. doi: 10.1016/j.jval.2018.01.012. Epub 2018 Mar 15.
• [16] 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.
• [17] The metastasis gene NEDD9 product acts through integrin 3 and Src to promote mesenchymal motility and inhibit amoeboid motility.J Cell Sci. 2012 Apr 1;125(Pt 7):1814-26. doi: 10.1242/jcs.101444. Epub 2012 Feb 10.
• [18] Dock3-NMDA receptor interaction as a target for glaucoma therapy.Histol Histopathol. 2017 Mar;32(3):215-221. doi: 10.14670/HH-11-820. Epub 2016 Sep 9.
• [19] DOCK3-related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia.Am J Med Genet A. 2018 Jan;176(1):241-245. doi: 10.1002/ajmg.a.38517. Epub 2017 Nov 12.
• [20] Peripheral assessment of the genes AQP4, PBP and TH in patients with Parkinson's disease.Neurochem Res. 2012 Mar;37(3):512-5. doi: 10.1007/s11064-011-0637-5. Epub 2011 Nov 15.
• [21] Drug-resistant genes and serotypes of pneumococcal strains of community-acquired pneumonia among adults in Japan.Respirology. 2006 Jul;11(4):429-36. doi: 10.1111/j.1440-1843.2006.00867.x.
• [22] Influence of diabetes mellitus on longitudinal atrophy and cognition in Parkinson's disease.J Neurol Sci. 2017 Jun 15;377:122-126. doi: 10.1016/j.jns.2017.04.010. Epub 2017 Apr 11.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [27] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [28] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [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] 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.
• [31] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.