Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUYTF4I)

• DOT Name: Rho GTPase-activating protein 31 (ARHGAP31)
• Synonyms: Cdc42 GTPase-activating protein
• Gene Name: ARHGAP31
• Related Disease:
  Adams-Oliver syndrome 1
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Coeliac disease
  Corpus callosum, agenesis of
  Multiple sclerosis
  Primary biliary cholangitis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic sclerosis
  Asthma
  Immune system disorder
  Adams-Oliver syndrome
  Breast cancer
  Breast carcinoma
  Acute myelogenous leukaemia
  Aplasia cutis congenita
  Coronary heart disease
• UniProt ID: RHG31_HUMAN
• Pfam ID: PF00620
• Sequence:
  MKNKGAKQKLKRKGAASAFGCDLTEYLESSGQDVPYVLKSCAEFIETHGIVDGIYRLSGV
  TSNIQRLRQEFGSDQCPDLTREVYLQDIHCVGSLCKLYFRELPNPLLTYELYEKFTEAVS
  HCPEEGQLARIQNVIQELPPSHYRTLEYLIRHLAHIASFSSKTNMHARNLALVWAPNLLR
  SKEIEATGCNGDAAFLAVRVQQVVIEFILNHVDQIFNNGAPGSLENDENRPIMKSLTLPA
  LSLPMKLVSLEEAQARSLATNHPARKERRENSLPEIVPPMGTLFHTVLELPDNKRKLSSK
  SKKWKSIFNLGRSGSDSKSKLSRNGSVFVRGQRLSVEKATIRPAKSMDSLCSVPVEGKET
  KGNFNRTVTTGGFFIPATKMHSTGTGSSCDLTKQEGEWGQEGMPPGAEGGFDVSSDRSHL
  QGAQARPPPEQLKVFRPVEDPESEQTAPKMLGMFYTSNDSPSKSVFTSSLFQMEPSPRNQ
  RKALNISEPFAVSVPLRVSAVISTNSTPCRTPPKELQSLSSLEEFSFHGSESGGWPEEEK
  PLGAETSAASVPKKAGLEDAKAVPEAPGTVECSKGLSQEPGAHLEEKKTPESSLSSQHLN
  ELEKRPNPEKVVEEGREAGEMESSTLQESPRARAEAVLLHEMDEDDLANALIWPEIQQEL
  KIIESEEELSSLPPPALKTSPIQPILESSLGPFIPSEPPGSLPCGSFPAPVSTPLEVWTR
  DPANQSTQGASTAASREKPEPEQGLHPDLASLAPLEIVPFEKASPQATVEVGGPGNLSPP
  LPPAPPPPTPLEESTPVLLSKGGPEREDSSRKLRTDLYIDQLKSQDSPEISSLCQGEEAT
  PRHSDKQNSKNAASEGKGCGFPSPTREVEIVSQEEEDVTHSVQEPSDCDEDDTVTDIAQH
  GLEMVEPWEEPQWVTSPLHSPTLKDAHKAQVQGLQGHQLEKRLSHRPSLRQSHSLDSKPT
  VKSQWTLEVPSSSSCANLETERNSDPLQPQAPRREITGWDEKALRSFREFSGLKGAEAPP
  NQKGPSGVQPNPAETSPISLAEGKELGTHLGHSSPQIRQGGVPGPESSKESSPSVQDSTS
  PGEHPAKLQLKSTECGPPKGKNRPSSLNLDPAIPIADLFWFENVASFSSPGMQVSEPGDP
  KVTWMTSSYCKADPWRVYSQDPQDLDIVAHALTGRRNSAPVSVSAVRTSFMVKMCQARAV
  PVIPPKIQYTQIPQPLPSQSSGENGVQPLERSQEGPSSTSGTTQKPAKDDSPSSLESSKE
  EKPKQDPGAIKSSPVDATAPCMCEGPTLSPEPGSSNLLSTQDAVVQCRKRMSETEPSGDN
  LLSSKLERPSGGSKPFHRSRPGRPQSLILFSPPFPIMDHLPPSSTVTDSKVLLSPIRSPT
  QTVSPGLLCGELAENTWVTPEGVTLRNKMTIPKNGQRLETSTSCFYQPQRRSVILDGRSG
  RQIE
• Function: Functions as a GTPase-activating protein (GAP) for RAC1 and CDC42. Required for cell spreading, polarized lamellipodia formation and cell migration.
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOU GTPase cycle (R-HSA-9013420)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adams-Oliver syndrome 1	DISC3I62	Strong	Autosomal dominant	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[2]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[3]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[6]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[2]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[7]
Asthma	DISW9QNS	moderate	Genetic Variation	[8]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[9]
Adams-Oliver syndrome	DISQO525	Supportive	Autosomal dominant	[10]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[11]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[12]
Aplasia cutis congenita	DISMDAYM	Limited	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho GTPase-activating protein 31 (ARHGAP31).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rho GTPase-activating protein 31 (ARHGAP31).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Rho GTPase-activating protein 31 (ARHGAP31).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Rho GTPase-activating protein 31 (ARHGAP31).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho GTPase-activating protein 31 (ARHGAP31).	[19]

1 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 Rho GTPase-activating protein 31 (ARHGAP31).	[16]

References

• [1] Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet. 1979;3(1):35-41. doi: 10.1002/ajmg.1320030109.
• [2] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [3] Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease.Nat Genet. 2011 Nov 6;43(12):1193-201. doi: 10.1038/ng.998.
• [4] Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.Hum Mutat. 2018 Sep;39(9):1246-1261. doi: 10.1002/humu.23567. Epub 2018 Jul 4.
• [5] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [6] Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2011 Mar 13;43(4):329-32. doi: 10.1038/ng.789.
• [7] GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways.Nat Commun. 2019 Oct 31;10(1):4955. doi: 10.1038/s41467-019-12760-y.
• [8] Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.Eur J Hum Genet. 2011 Apr;19(4):458-64. doi: 10.1038/ejhg.2010.191. Epub 2010 Dec 8.
• [9] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [10] Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies. Am J Hum Genet. 2011 May 13;88(5):574-85. doi: 10.1016/j.ajhg.2011.04.013.
• [11] CdGAP/ARHGAP31 is regulated by RSK phosphorylation and binding to 14-3-3 adaptor protein.Oncotarget. 2018 Jan 10;9(14):11646-11664. doi: 10.18632/oncotarget.24126. eCollection 2018 Feb 20.
• [12] 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.
• [13] Validation study of genetic associations with coronary artery disease on chromosome 3q13-21 and potential effect modification by smoking.Ann Hum Genet. 2009 Nov;73(Pt 6):551-8. doi: 10.1111/j.1469-1809.2009.00540.x. Epub 2009 Aug 25.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.