Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVV7KJO)

DOT Name ADP-ribosylation factor 6 (ARF6)
Synonyms EC 3.6.5.2
Gene Name ARF6
Related Disease
Carcinoma of liver and intrahepatic biliary tract ( )
Diabetic retinopathy ( )
Liver cancer ( )
Melanoma ( )
Nephropathy ( )
Vascular disease ( )
Androgen insensitivity syndrome ( )
Benign prostatic hyperplasia ( )
Breast cancer ( )
Breast carcinoma ( )
Colorectal carcinoma ( )
Crohn disease ( )
Diabetic kidney disease ( )
Esophageal adenocarcinoma ( )
Familial infantile myoclonic epilepsy ( )
Fibrosarcoma ( )
Glioma ( )
Head and neck cancer ( )
Head and neck carcinoma ( )
Head-neck squamous cell carcinoma ( )
Hepatocellular carcinoma ( )
High blood pressure ( )
Hyperglycemia ( )
Lung cancer ( )
Lung carcinoma ( )
Metastatic malignant neoplasm ( )
Neoplasm ( )
Uveal Melanoma ( )
Invasive breast carcinoma ( )
Nasopharyngeal carcinoma ( )
Niemann-Pick disease type C ( )
Advanced cancer ( )
Gastric cancer ( )
Hereditary hemochromatosis ( )
Pancreatic cancer ( )
Stomach cancer ( )
UniProt ID
ARF6_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1E0S; 2A5D; 2A5F; 2A5G; 2BAO; 2BAU; 2J5X; 2W83; 3LVQ; 3LVR; 3N5C; 3PCR; 4FME; 4KAX; 6BBP; 6BBQ; 6PAU; 7RK3; 7XRD
EC Number
3.6.5.2
Pfam ID
PF00025
Sequence
MGKVLSKIFGNKEMRILMLGLDAAGKTTILYKLKLGQSVTTIPTVGFNVETVTYKNVKFN
VWDVGGQDKIRPLWRHYYTGTQGLIFVVDCADRDRIDEARQELHRIINDREMRDAIILIF
ANKQDLPDAMKPHEIQEKLGLTRIRDRNWYVQPSCATSGDGLYEGLTWLTSNYKS
Function
GTP-binding protein involved in protein trafficking that regulates endocytic recycling and cytoskeleton remodeling. GTP-bound form plays an important role in the transport of multiple palmitoylated proteins form the Golgi to the plasma membrane. Required for normal completion of mitotic cytokinesis. Plays a role in the reorganization of the actin cytoskeleton and the formation of stress fibers. Involved in the regulation of dendritic spine development, contributing to the regulation of dendritic branching and filopodia extension. Potentiates the neurite outgrowth in primary neurons by interacting with the molecular adapter APBB1. Plays an important role in membrane trafficking, during junctional remodeling and epithelial polarization. Regulates surface levels of adherens junction proteins such as CDH1. Required for NTRK1 sorting to the recycling pathway from early endosomes; (Microbial infection) Functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase; (Microbial infection) Plays a key role in the endocytosis of enterovirus 71 and thus viral entry into brain microvascular endothelial cells.
Tissue Specificity Ubiquitous, with higher levels in heart, substantia nigra, and kidney.
KEGG Pathway
Ras sig.ling pathway (hsa04014 )
Phospholipase D sig.ling pathway (hsa04072 )
Endocytosis (hsa04144 )
Fc gamma R-mediated phagocytosis (hsa04666 )
Pathogenic Escherichia coli infection (hsa05130 )
Shigellosis (hsa05131 )
Salmonella infection (hsa05132 )
Yersinia infection (hsa05135 )
Reactome Pathway
Clathrin-mediated endocytosis (R-HSA-8856828 )
MET receptor recycling (R-HSA-8875656 )
TBC/RABGAPs (R-HSA-8854214 )

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Carcinoma of liver and intrahepatic biliary tract DIS8WA0W Definitive Altered Expression [1]
Diabetic retinopathy DISHGUJM Definitive Biomarker [2]
Liver cancer DISDE4BI Definitive Altered Expression [1]
Melanoma DIS1RRCY Definitive Biomarker [3]
Nephropathy DISXWP4P Definitive Biomarker [4]
Vascular disease DISVS67S Definitive Biomarker [2]
Androgen insensitivity syndrome DISUZBBO Strong Biomarker [5]
Benign prostatic hyperplasia DISI3CW2 Strong Altered Expression [6]
Breast cancer DIS7DPX1 Strong Altered Expression [7]
Breast carcinoma DIS2UE88 Strong Biomarker [8]
Colorectal carcinoma DIS5PYL0 Strong Genetic Variation [9]
Crohn disease DIS2C5Q8 Strong Genetic Variation [10]
Diabetic kidney disease DISJMWEY Strong Biomarker [11]
Esophageal adenocarcinoma DISODWFP Strong Biomarker [12]
Familial infantile myoclonic epilepsy DISELJ0F Strong Genetic Variation [13]
Fibrosarcoma DISWX7MU Strong Biomarker [14]
Glioma DIS5RPEH Strong Biomarker [15]
Head and neck cancer DISBPSQZ Strong Biomarker [16]
Head and neck carcinoma DISOU1DS Strong Biomarker [16]
Head-neck squamous cell carcinoma DISF7P24 Strong Altered Expression [17]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [18]
High blood pressure DISY2OHH Strong Biomarker [19]
Hyperglycemia DIS0BZB5 Strong Altered Expression [11]
Lung cancer DISCM4YA Strong Altered Expression [20]
Lung carcinoma DISTR26C Strong Altered Expression [20]
Metastatic malignant neoplasm DIS86UK6 Strong Biomarker [21]
Neoplasm DISZKGEW Strong Biomarker [3]
Uveal Melanoma DISA7ZGL Strong Biomarker [22]
Invasive breast carcinoma DISANYTW moderate Biomarker [23]
Nasopharyngeal carcinoma DISAOTQ0 moderate Biomarker [24]
Niemann-Pick disease type C DIS492ZO moderate Biomarker [24]
Advanced cancer DISAT1Z9 Limited Biomarker [25]
Gastric cancer DISXGOUK Limited Biomarker [26]
Hereditary hemochromatosis DISVG5MT Limited Biomarker [27]
Pancreatic cancer DISJC981 Limited Biomarker [28]
Stomach cancer DISKIJSX Limited Biomarker [26]
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⏷ Show the Full List of 36 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 1 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Cisplatin DMRHGI9 Approved ADP-ribosylation factor 6 (ARF6) affects the response to substance of Cisplatin. [46]
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1 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 ADP-ribosylation factor 6 (ARF6). [29]
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15 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of ADP-ribosylation factor 6 (ARF6). [30]
Tretinoin DM49DUI Approved Tretinoin affects the expression of ADP-ribosylation factor 6 (ARF6). [31]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of ADP-ribosylation factor 6 (ARF6). [32]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of ADP-ribosylation factor 6 (ARF6). [33]
Estradiol DMUNTE3 Approved Estradiol increases the expression of ADP-ribosylation factor 6 (ARF6). [34]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of ADP-ribosylation factor 6 (ARF6). [35]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of ADP-ribosylation factor 6 (ARF6). [36]
Bortezomib DMNO38U Approved Bortezomib increases the expression of ADP-ribosylation factor 6 (ARF6). [37]
Diethylstilbestrol DMN3UXQ Approved Diethylstilbestrol increases the expression of ADP-ribosylation factor 6 (ARF6). [38]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of ADP-ribosylation factor 6 (ARF6). [40]
Tamibarotene DM3G74J Phase 3 Tamibarotene affects the expression of ADP-ribosylation factor 6 (ARF6). [31]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of ADP-ribosylation factor 6 (ARF6). [42]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of ADP-ribosylation factor 6 (ARF6). [43]
Glyphosate DM0AFY7 Investigative Glyphosate increases the expression of ADP-ribosylation factor 6 (ARF6). [44]
Lithium chloride DMHYLQ2 Investigative Lithium chloride increases the expression of ADP-ribosylation factor 6 (ARF6). [45]
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⏷ Show the Full List of 15 Drug(s)
3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Propranolol DM79NTF Approved Propranolol affects the localization of ADP-ribosylation factor 6 (ARF6). [39]
phorbol 12-myristate 13-acetate DMJWD62 Phase 2 phorbol 12-myristate 13-acetate affects the localization of ADP-ribosylation factor 6 (ARF6). [41]
Fmet-leu-phe DMQ391A Investigative Fmet-leu-phe affects the localization of ADP-ribosylation factor 6 (ARF6). [41]
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References

1 Arf6-driven endocytic recycling of CD147 determines HCC malignant phenotypes.J Exp Clin Cancer Res. 2019 Nov 21;38(1):471. doi: 10.1186/s13046-019-1464-9.
2 Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy.J Clin Invest. 2017 Dec 1;127(12):4569-4582. doi: 10.1172/JCI91770. Epub 2017 Oct 23.
3 The Small GTPase ARF6 Activates PI3K in Melanoma to Induce a Prometastatic State.Cancer Res. 2019 Jun 1;79(11):2892-2908. doi: 10.1158/0008-5472.CAN-18-3026. Epub 2019 May 2.
4 ARF6 mediates nephrin tyrosine phosphorylation-induced podocyte cellular dynamics.PLoS One. 2017 Sep 7;12(9):e0184575. doi: 10.1371/journal.pone.0184575. eCollection 2017.
5 EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment.J Cell Sci. 2017 Nov 1;130(21):3663-3675. doi: 10.1242/jcs.207423. Epub 2017 Sep 21.
6 A NAV2729-sensitive mechanism promotes adrenergic smooth muscle contraction and growth of stromal cells in the human prostate.J Biol Chem. 2019 Aug 9;294(32):12231-12249. doi: 10.1074/jbc.RA119.007958. Epub 2019 Jun 26.
7 Roles of Arf6 in cancer cell invasion, metastasis and proliferation.Life Sci. 2017 Aug 1;182:80-84. doi: 10.1016/j.lfs.2017.06.008. Epub 2017 Jun 15.
8 Role of ARHGAP24 in ADP Ribosylation Factor 6 (ARF6)-dependent Pseudopod Formation in Human Breast Carcinoma Cells.Anticancer Res. 2017 Sep;37(9):4837-4844. doi: 10.21873/anticanres.11891.
9 Involvement of small ArfGAP1 (SMAP1), a novel Arf6-specific GTPase-activating protein, in microsatellite instability oncogenesis.Oncogene. 2014 May 22;33(21):2758-67. doi: 10.1038/onc.2013.211. Epub 2013 Jun 10.
10 Peptidoglycan Metabolite Photoaffinity Reporters Reveal Direct Binding to Intracellular Pattern Recognition Receptors and Arf GTPases.ACS Chem Biol. 2019 Mar 15;14(3):405-414. doi: 10.1021/acschembio.8b01038. Epub 2019 Feb 20.
11 Small GTPase Arf6 regulates diabetes-induced cholesterol accumulation in podocytes.J Cell Physiol. 2019 Dec;234(12):23559-23570. doi: 10.1002/jcp.28924. Epub 2019 Jun 17.
12 APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma.Cancer Res. 2019 Sep 1;79(17):4426-4438. doi: 10.1158/0008-5472.CAN-19-0237. Epub 2019 Jul 15.
13 TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet. 2010 Sep 10;87(3):365-70. doi: 10.1016/j.ajhg.2010.07.020. Epub 2010 Aug 19.
14 Arf6, JIP3, and dynein shape and mediate macropinocytosis.Mol Biol Cell. 2019 Jun 1;30(12):1477-1489. doi: 10.1091/mbc.E19-01-0022. Epub 2019 Apr 10.
15 ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway.Cancer Res. 2009 Feb 1;69(3):794-801. doi: 10.1158/0008-5472.CAN-08-2110. Epub 2009 Jan 20.
16 Inhibition of epithelial-mesenchymal transition by cetuximab via the EGFR-GEP100-Arf6-AMAP1 pathway in head and neck cancer.Head Neck. 2017 Mar;39(3):476-485. doi: 10.1002/hed.24626. Epub 2016 Nov 23.
17 High level expression of AMAP1 protein correlates with poor prognosis and survival after surgery of head and neck squamous cell carcinoma patients.Cell Commun Signal. 2014 Mar 12;12:17. doi: 10.1186/1478-811X-12-17.
18 ASAP3 is a downstream target of HIF-1 and is critical for progression of lung adenocarcinoma.Onco Targets Ther. 2019 Jul 17;12:5793-5803. doi: 10.2147/OTT.S199603. eCollection 2019.
19 CLIC4/Arf6 Pathway.Circ Res. 2019 Jan 4;124(1):52-65. doi: 10.1161/CIRCRESAHA.118.313705.
20 DDEFL1 correlated with Rho GTPases activity in breast cancer.Oncotarget. 2017 Oct 26;8(68):112487-112497. doi: 10.18632/oncotarget.22095. eCollection 2017 Dec 22.
21 IGF2BP3-mediated translation in cell protrusions promotes cell invasiveness and metastasis of pancreatic cancer.Oncotarget. 2014 Aug 30;5(16):6832-45. doi: 10.18632/oncotarget.2257.
22 ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma.Cancer Cell. 2016 Jun 13;29(6):889-904. doi: 10.1016/j.ccell.2016.04.015. Epub 2016 Jun 2.
23 Targeting AMAP1 and cortactin binding bearing an atypical src homology 3/proline interface for prevention of breast cancer invasion and metastasis.Proc Natl Acad Sci U S A. 2006 May 2;103(18):7036-41. doi: 10.1073/pnas.0509166103. Epub 2006 Apr 24.
24 ARF6-mediated endosome recycling reverses lipid accumulation defects in Niemann-Pick Type C disease.PLoS One. 2009;4(4):e5193. doi: 10.1371/journal.pone.0005193. Epub 2009 Apr 14.
25 HGF-induced migration depends on the PI(3,4,5)P(3)-binding microexon-spliced variant of the Arf6 exchange factor cytohesin-1.J Cell Biol. 2019 Jan 7;218(1):285-298. doi: 10.1083/jcb.201804106. Epub 2018 Nov 7.
26 Knockdown of Arf6 increases drug sensitivity and inhibits proliferation, migration and invasion in gastric cancer SGC-7901 cells.Oncol Lett. 2018 Feb;15(2):2147-2152. doi: 10.3892/ol.2017.7558. Epub 2017 Dec 8.
27 EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth.Nat Commun. 2017 Mar 10;8:14688. doi: 10.1038/ncomms14688.
28 Circulating pancreatic cancer exosomal RNAs for detection of pancreatic cancer.Mol Oncol. 2019 Feb;13(2):212-227. doi: 10.1002/1878-0261.12398. Epub 2018 Nov 15.
29 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.
30 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
31 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
32 Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
33 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.
34 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.
35 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.
36 Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
37 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
38 Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
39 An effector domain mutant of Arf6 implicates phospholipase D in endosomal membrane recycling. Mol Biol Cell. 2006 Jan;17(1):327-35. doi: 10.1091/mbc.e05-06-0523. Epub 2005 Nov 9.
40 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
41 A regulatory role for ADP-ribosylation factor 6 (ARF6) in activation of the phagocyte NADPH oxidase. J Biol Chem. 2000 Oct 20;275(42):32566-71. doi: 10.1074/jbc.M005406200.
42 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
43 An integrative transcriptomic analysis reveals bisphenol A exposure-induced dysregulation of microRNA expression in human endometrial cells. Toxicol In Vitro. 2017 Jun;41:133-142. doi: 10.1016/j.tiv.2017.02.012. Epub 2017 Feb 24.
44 Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
45 Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.
46 Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.