Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8JH4TY)

DOT Name Rho GTPase-activating protein 29 (ARHGAP29)
Synonyms PTPL1-associated RhoGAP protein 1; Rho-type GTPase-activating protein 29
Gene Name ARHGAP29
Related Disease
Obsolete cleft lip with or without cleft palate ( )
Isolated cleft lip ( )
Isolated cleft palate ( )
Mantle cell lymphoma ( )
Cleft lip/palate ( )
Neoplasm ( )
UniProt ID
RHG29_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF00130 ; PF00620
Sequence
MIAHKQKKTKKKRAWASGQLSTDITTSEMGLKSLSSNSIFDPDYIKELVNDIRKFSHMLL
YLKEAIFSDCFKEVIHIRLEELLRVLKSIMNKHQNLNSVDLQNAAEMLTAKVKAVNFTEV
NEENKNDLFQEVFSSIETLAFTFGNILTNFLMGDVGNDSLLRLPVSRETKSFENVSVESV
DSSSEKGNFSPLELDNVLLKNTDSIELALSYAKTWSKYTKNIVSWVEKKLNLELESTRNM
VKLAEATRTNIGIQEFMPLQSLFTNALLNDIESSHLLQQTIAALQANKFVQPLLGRKNEM
EKQRKEIKELWKQEQNKMLEAENALKKAKLLCMQRQDEYEKAKSSMFRAEEEHLSSSGGL
AKNLNKQLEKKRRLEEEALQKVEEANELYKVCVTNVEERRNDLENTKREILAQLRTLVFQ
CDLTLKAVTVNLFHMQHLQAASLADSLQSLCDSAKLYDPGQEYSEFVKATNSTEEEKVDG
NVNKHLNSSQPSGFGPANSLEDVVRLPDSSNKIEEDRCSNSADITGPSFIRSWTFGMFSD
SESTGGSSESRSLDSESISPGDFHRKLPRTPSSGTMSSADDLDEREPPSPSETGPNSLGT
FKKTLMSKAALTHKFRKLRSPTKCRDCEGIVVFQGVECEECLLVCHRKCLENLVIICGHQ
KLPGKIHLFGAEFTQVAKKEPDGIPFILKICASEIENRALCLQGIYRVCGNKIKTEKLCQ
ALENGMHLVDISEFSSHDICDVLKLYLRQLPEPFILFRLYKEFIDLAKEIQHVNEEQETK
KNSLEDKKWPNMCIEINRILLKSKDLLRQLPASNFNSLHFLIVHLKRVVDHAEENKMNSK
NLGVIFGPSLIRPRPTTAPITISSLAEYSNQARLVEFLITYSQKIFDGSLQPQDVMCSIG
VVDQGCFPKPLLSPEERDIERSMKSLFFSSKEDIHTSESESKIFERATSFEESERKQNAL
GKCDACLSDKAQLLLDQEAESASQKIEDGKTPKPLSLKSDRSTNNVERHTPRTKIRPVSL
PVDRLLLASPPNERNGRNMGNVNLDKFCKNPAFEGVNRKDAATTVCSKFNGFDQQTLQKI
QDKQYEQNSLTAKTTMIMPSALQEKGVTTSLQISGDHSINATQPSKPYAEPVRSVREASE
RRSSDSYPLAPVRAPRTLQPQHWTTFYKPHAPIISIRGNEEKPASPSAAVPPGTDHDPHG
LVVKSMPDPDKASACPGQATGQPKEDSEELGLPDVNPMCQRPRLKRMQQFEDLEGEIPQF
V
Function
GTPase activator for the Rho-type GTPases by converting them to an inactive GDP-bound state. Has strong activity toward RHOA, and weaker activity toward RAC1 and CDC42. May act as a specific effector of RAP2A to regulate Rho. In concert with RASIP1, suppresses RhoA signaling and dampens ROCK and MYH9 activities in endothelial cells and plays an essential role in blood vessel tubulogenesis.
Tissue Specificity Widely expressed. Highly expressed in skeletal muscle and heart. Expressed at intermediate level in placenta, liver and pancreas. Weakly expressed in brain, lung and kidney.
KEGG Pathway
Adherens junction (hsa04520 )
Reactome Pathway
CDC42 GTPase cycle (R-HSA-9013148 )
RAC1 GTPase cycle (R-HSA-9013149 )
RHOA GTPase cycle (R-HSA-8980692 )

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Obsolete cleft lip with or without cleft palate DISGXFHX Definitive Autosomal dominant [1]
Isolated cleft lip DIS2O2JV Strong Genetic Variation [2]
Isolated cleft palate DISV80CD Strong Biomarker [3]
Mantle cell lymphoma DISFREOV moderate Posttranslational Modification [4]
Cleft lip/palate DIS14IG3 Limited SusceptibilityMutation [5]
Neoplasm DISZKGEW Limited Altered Expression [6]
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⏷ Show the Full List of 6 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
6 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the methylation of Rho GTPase-activating protein 29 (ARHGAP29). [7]
Quercetin DM3NC4M Approved Quercetin increases the phosphorylation of Rho GTPase-activating protein 29 (ARHGAP29). [13]
Decitabine DMQL8XJ Approved Decitabine affects the methylation of Rho GTPase-activating protein 29 (ARHGAP29). [4]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of Rho GTPase-activating protein 29 (ARHGAP29). [22]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Rho GTPase-activating protein 29 (ARHGAP29). [13]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Rho GTPase-activating protein 29 (ARHGAP29). [26]
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⏷ Show the Full List of 6 Drug(s)
19 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [8]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [9]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [10]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [11]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [12]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of Rho GTPase-activating protein 29 (ARHGAP29). [14]
Triclosan DMZUR4N Approved Triclosan increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [15]
Folic acid DMEMBJC Approved Folic acid affects the expression of Rho GTPase-activating protein 29 (ARHGAP29). [17]
Cocaine DMSOX7I Approved Cocaine decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [18]
Simvastatin DM30SGU Approved Simvastatin decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [19]
Rofecoxib DM3P5DA Approved Rofecoxib decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [20]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [21]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [23]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [24]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [25]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [27]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [28]
Lithium chloride DMHYLQ2 Investigative Lithium chloride increases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [29]
Bilirubin DMI0V4O Investigative Bilirubin decreases the expression of Rho GTPase-activating protein 29 (ARHGAP29). [30]
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⏷ Show the Full List of 19 Drug(s)

References

1 Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome-wide association on chromosome 1p22. Birth Defects Res A Clin Mol Teratol. 2012 Nov;94(11):934-42. doi: 10.1002/bdra.23076. Epub 2012 Sep 24.
2 Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci.Nat Genet. 2012 Sep;44(9):968-71. doi: 10.1038/ng.2360. Epub 2012 Aug 5.
3 Exome sequencing provides additional evidence for the involvement of ARHGAP29 in Mendelian orofacial clefting and extends the phenotypic spectrum to isolated cleft palate.Birth Defects Res. 2017 Jan 20;109(1):27-37. doi: 10.1002/bdra.23596.
4 Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle-cell lymphomas. Haematologica. 2007 Apr;92(4):460-8. doi: 10.3324/haematol.10337.
5 Impact of rare variants in ARHGAP29 to the etiology of oral clefts: role of loss-of-function vs missense variants.Clin Genet. 2017 May;91(5):683-689. doi: 10.1111/cge.12823. Epub 2016 Jul 26.
6 YAP Regulates Actin Dynamics through ARHGAP29 and Promotes Metastasis.Cell Rep. 2017 May 23;19(8):1495-1502. doi: 10.1016/j.celrep.2017.04.075.
7 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.
8 Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
9 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.
10 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
11 Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
12 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.
13 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.
14 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
15 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
16 Promoter methylation of PARG1, a novel candidate tumor suppressor gene in mantle-cell lymphomas. Haematologica. 2007 Apr;92(4):460-8. doi: 10.3324/haematol.10337.
17 Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
18 Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
19 Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
20 Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
21 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.
22 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.
23 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
24 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.
25 Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
26 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.
27 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.
28 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
29 Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.
30 Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.