Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZTS3PA)

• DOT Name: Dedicator of cytokinesis protein 2 (DOCK2)
• Gene Name: DOCK2
• Related Disease:
  DOCK2 deficiency
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  B-cell neoplasm
  Familial prostate carcinoma
  Follicular lymphoma
  Haematological malignancy
  Leukemia
  Neoplasm
  Obesity
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Rheumatoid arthritis
  Severe combined immunodeficiency
  Synovitis
  Bacterial infection
  Colorectal carcinoma
  Esophageal adenocarcinoma
  HIV infectious disease
  Post-traumatic stress disorder
  Small lymphocytic lymphoma
• UniProt ID: DOCK2_HUMAN
• PDB ID: 2RQR; 2YIN; 3A98; 3B13; 6TGB; 6TGC
• Pfam ID: PF06920 ; PF20422 ; PF20421 ; PF14429 ; PF16172 ; PF07653
• Sequence:
  MAPWRKADKERHGVAIYNFQGSGAPQLSLQIGDVVRIQETCGDWYRGYLIKHKMLQGIFP
  KSFIHIKEVTVEKRRNTENIIPAEIPLAQEVTTTLWEWGSIWKQLYVASKKERFLQVQSM
  MYDLMEWRSQLLSGTLPKDELKELKQKVTSKIDYGNKILELDLIVRDEDGNILDPDNTSV
  ISLFHAHEEATDKITERIKEEMSKDQPDYAMYSRISSSPTHSLYVFVRNFVCRIGEDAEL
  FMSLYDPNKQTVISENYLVRWGSRGFPKEIEMLNNLKVVFTDLGNKDLNRDKIYLICQIV
  RVGKMDLKDTGAKKCTQGLRRPFGVAVMDITDIIKGKAESDEEKQHFIPFHPVTAENDFL
  HSLLGKVIASKGDSGGQGLWVTMKMLVGDIIQIRKDYPHLVDRTTVVARKLGFPEIIMPG
  DVRNDIYITLLQGDFDKYNKTTQRNVEVIMCVCAEDGKTLPNAICVGAGDKPMNEYRSVV
  YYQVKQPRWMETVKVAVPIEDMQRIHLRFMFRHRSSLESKDKGEKNFAMSYVKLMKEDGT
  TLHDGFHDLVVLKGDSKKMEDASAYLTLPSYRHHVENKGATLSRSSSSVGGLSVSSRDVF
  SISTLVCSTKLTQNVGLLGLLKWRMKPQLLQENLEKLKIVDGEEVVKFLQDTLDALFNIM
  MEHSQSDEYDILVFDALIYIIGLIADRKFQHFNTVLEAYIQQHFSATLAYKKLMTVLKTY
  LDTSSRGEQCEPILRTLKALEYVFKFIVRSRTLFSQLYEGKEQMEFEESMRRLFESINNL
  MKSQYKTTILLQVAALKYIPSVLHDVEMVFDAKLLSQLLYEFYTCIPPVKLQKQKVQSMN
  EIVQSNLFKKQECRDILLPVITKELKELLEQKDDMQHQVLERKYCVELLNSILEVLSYQD
  AAFTYHHIQEIMVQLLRTVNRTVITMGRDHILISHFVACMTAILNQMGDQHYSFYIETFQ
  TSSELVDFLMETFIMFKDLIGKNVYPGDWMAMSMVQNRVFLRAINKFAETMNQKFLEHTN
  FEFQLWNNYFHLAVAFITQDSLQLEQFSHAKYNKILNKYGDMRRLIGFSIRDMWYKLGQN
  KICFIPGMVGPILEMTLIPEAELRKATIPIFFDMMLCEYQRSGDFKKFENEIILKLDHEV
  EGGRGDEQYMQLLESILMECAAEHPTIAKSVENFVNLVKGLLEKLLDYRGVMTDESKDNR
  MSCTVNLLNFYKDNNREEMYIRYLYKLRDLHLDCDNYTEAAYTLLLHTWLLKWSDEQCAS
  QVMQTGQQHPQTHRQLKETLYETIIGYFDKGKMWEEAISLCKELAEQYEMEIFDYELLSQ
  NLIQQAKFYESIMKILRPKPDYFAVGYYGQGFPSFLRNKVFIYRGKEYERREDFQMQLMT
  QFPNAEKMNTTSAPGDDVKNAPGQYIQCFTVQPVLDEHPRFKNKPVPDQIINFYKSNYVQ
  RFHYSRPVRRGTVDPENEFASMWIERTSFVTAYKLPGILRWFEVVHMSQTTISPLENAIE
  TMSTANEKILMMINQYQSDETLPINPLSMLLNGIVDPAVMGGFAKYEKAFFTEEYVRDHP
  EDQDKLTHLKDLIAWQIPFLGAGIKIHEKRVSDNLRPFHDRMEECFKNLKMKVEKEYGVR
  EMPDFDDRRVGRPRSMLRSYRQMSIISLASMNSDCSTPSKPTSESFDLELASPKTPRVEQ
  EEPISPGSTLPEVKLRRSKKRTKRSSVVFADEKAAAESDLKRLSRKHEFMSDTNLSEHAA
  IPLKASVLSQMSFASQSMPTIPALALSVAGIPGLDEANTSPRLSQTFLQLSDGDKKTLTR
  KKVNQFFKTMLASKSAEEGKQIPDSLSTDL
• Function: Involved in cytoskeletal rearrangements required for lymphocyte migration in response of chemokines. Activates RAC1 and RAC2, but not CDC42, by functioning as a guanine nucleotide exchange factor (GEF), which exchanges bound GDP for free GTP. May also participate in IL2 transcriptional activation via the activation of RAC2.
• Tissue Specificity: Specifically expressed in hematopoietic cells. Highly expressed in peripheral blood leukocytes, and expressed at intermediate level in thymus and spleen. Expressed at very low level in the small intestine and colon.
• KEGG Pathway: Chemokine sig.ling pathway (hsa04062)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  RHOA GTPase cycle (R-HSA-8980692)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  Nef and signal transduction (R-HSA-164944)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DOCK2 deficiency	DISP9CBE	Definitive	Autosomal recessive	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[6]
Follicular lymphoma	DISVEUR6	Strong	Biomarker	[5]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[5]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Obesity	DIS47Y1K	Strong	Biomarker	[9]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[10]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[11]
Synovitis	DISW2GPY	Strong	Biomarker	[12]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[8]
Esophageal adenocarcinoma	DISODWFP	moderate	Biomarker	[13]
HIV infectious disease	DISO97HC	moderate	Biomarker	[3]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[14]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[15]

10 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 Dedicator of cytokinesis protein 2 (DOCK2).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[26]
Choline	DM5D9YK	Investigative	Choline affects the expression of Dedicator of cytokinesis protein 2 (DOCK2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Dedicator of cytokinesis protein 2 (DOCK2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dedicator of cytokinesis protein 2 (DOCK2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dedicator of cytokinesis protein 2 (DOCK2).	[25]

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] FLT3-ITD cooperates with Rac1 to modulate the sensitivity of leukemic cells to chemotherapeutic agents via regulation of DNA repair pathways.Haematologica. 2019 Dec;104(12):2418-2428. doi: 10.3324/haematol.2018.208843. Epub 2019 Apr 11.
• [3] Dock2 in the development of inflammation and cancer.Eur J Immunol. 2018 Jun;48(6):915-922. doi: 10.1002/eji.201747157. Epub 2018 Apr 11.
• [4] Dedicator of Cytokinesis 2 in Cell Signaling Regulation and Disease Development.J Cell Physiol. 2017 Aug;232(8):1931-1940. doi: 10.1002/jcp.25512. Epub 2017 Feb 28.
• [5] DOCK2 regulates cell proliferation through Rac and ERK activation in B cell lymphoma.Biochem Biophys Res Commun. 2010 Apr 23;395(1):111-5. doi: 10.1016/j.bbrc.2010.03.148. Epub 2010 Mar 27.
• [6] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [7] DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines.Blood. 2002 Dec 1;100(12):3968-74. doi: 10.1182/blood-2001-11-0032. Epub 2002 Jun 28.
• [8] Overexpression of dedicator of cytokinesis 2 correlates with good prognosis in colorectal cancer associated with more prominent CD8(+) lymphocytes infiltration: a colorectal cancer analysis.J Cell Biochem. 2018 Nov;119(11):8962-8970. doi: 10.1002/jcb.27151. Epub 2018 Aug 4.
• [9] DOCK2 deficiency mitigates HFD-induced obesity by reducing adipose tissue inflammation and increasing energy expenditure.J Lipid Res. 2017 Sep;58(9):1777-1784. doi: 10.1194/jlr.M073049. Epub 2017 Jul 17.
• [10] A noncanonical role for the engulfment gene ELMO1 in neutrophils that promotes inflammatory arthritis.Nat Immunol. 2019 Feb;20(2):141-151. doi: 10.1038/s41590-018-0293-x. Epub 2019 Jan 14.
• [11] DOCK family proteins: key players in immune surveillance mechanisms.Int Immunol. 2020 Jan 9;32(1):5-15. doi: 10.1093/intimm/dxz067.
• [12] Multivariate genome-wide association analysis identifies novel and relevant variants associated with anterior cruciate ligament rupture risk in the dog model.BMC Genet. 2018 Jun 26;19(1):39. doi: 10.1186/s12863-018-0626-7.
• [13] Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.Nat Genet. 2013 May;45(5):478-86. doi: 10.1038/ng.2591. Epub 2013 Mar 24.
• [14] Genomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD.Acta Psychiatr Scand. 2017 Nov;136(5):493-505. doi: 10.1111/acps.12778. Epub 2017 Aug 9.
• [15] Wnt5a induces ROR1 to recruit DOCK2 to activate Rac1/2 in chronic lymphocytic leukemia.Blood. 2018 Jul 12;132(2):170-178. doi: 10.1182/blood-2017-12-819383. Epub 2018 Apr 20.
• [16] 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.
• [17] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [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] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [22] 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.
• [23] 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.
• [24] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [25] 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.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Lymphocyte gene expression in subjects fed a low-choline diet differs between those who develop organ dysfunction and those who do not. Am J Clin Nutr. 2007 Jul;86(1):230-9. doi: 10.1093/ajcn/86.1.230.