Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ8POG0)

• DOT Name: Rho GTPase-activating protein 35 (ARHGAP35)
• Synonyms: Glucocorticoid receptor DNA-binding factor 1; Glucocorticoid receptor repression factor 1; GRF-1; Rho GAP p190A; p190-A
• Gene Name: ARHGAP35
• Related Disease:
  Lung adenocarcinoma
  Bone osteosarcoma
  Melanoma
  Osteosarcoma
  Progressive non-fluent aphasia
  Advanced cancer
  Colorectal carcinoma
  Neoplasm
  Glioma
• UniProt ID: RHG35_HUMAN
• PDB ID: 2K85; 3C5H; 3FK2; 6PXC; 6WAY; 8DGQ
• Pfam ID: PF00071 ; PF00620 ; PF16512 ; PF19518
• Sequence:
  MMMARKQDVRIPTYNISVVGLSGTEKEKGQCGIGKSCLCNRFVRPSADEFHLDHTSVLST
  SDFGGRVVNNDHFLYWGEVSRSLEDCVECKMHIVEQTEFIDDQTFQPHRSTALQPYIKRA
  AATKLASAEKLMYFCTDQLGLEQDFEQKQMPDGKLLVDGFLLGIDVSRGMNRNFDDQLKF
  VSNLYNQLAKTKKPIVVVLTKCDEGVERYIRDAHTFALSKKNLQVVETSARSNVNVDLAF
  STLVQLIDKSRGKTKIIPYFEALKQQSQQIATAKDKYEWLVSRIVKNHNENWLSVSRKMQ
  ASPEYQDYVYLEGTQKAKKLFLQHIHRLKHEHIERRRKLYLAALPLAFEALIPNLDEIDH
  LSCIKAKKLLETKPEFLKWFVVLEETPWDATSHIDNMENERIPFDLMDTVPAEQLYEAHL
  EKLRNERKRVEMRRAFKENLETSPFITPGKPWEEARSFIMNEDFYQWLEESVYMDIYGKH
  QKQIIDKAKEEFQELLLEYSELFYELELDAKPSKEKMGVIQDVLGEEQRFKALQKLQAER
  DALILKHIHFVYHPTKETCPSCPACVDAKIEHLISSRFIRPSDRNQKNSLSDPNIDRINL
  VILGKDGLARELANEIRALCTNDDKYVIDGKMYELSLRPIEGNVRLPVNSFQTPTFQPHG
  CLCLYNSKESLSYVVESIEKSRESTLGRRDNHLVHLPLTLILVNKRGDTSGETLHSLIQQ
  GQQIASKLQCVFLDPASAGIGYGRNINEKQISQVLKGLLDSKRNLNLVSSTASIKDLADV
  DLRIVMCLMCGDPFSADDILFPVLQSQTCKSSHCGSNNSVLLELPIGLHKKRIELSVLSY
  HSSFSIRKSRLVHGYIVFYSAKRKASLAMLRAFLCEVQDIIPIQLVALTDGAVDVLDNDL
  SREQLTEGEEIAQEIDGRFTSIPCSQPQHKLEIFHPFFKDVVEKKNIIEATHMYDNAAEA
  CSTTEEVFNSPRAGSPLCNSNLQDSEEDIEPSYSLFREDTSLPSLSKDHSKLSMELEGND
  GLSFIMSNFESKLNNKVPPPVKPKPPVHFEITKGDLSYLDQGHRDGQRKSVSSSPWLPQD
  GFDPSDYAEPMDAVVKPRNEEENIYSVPHDSTQGKIITIRNINKAQSNGSGNGSDSEMDT
  SSLERGRKVSIVSKPVLYRTRCTRLGRFASYRTSFSVGSDDELGPIRKKEEDQASQGYKG
  DNAVIPYETDEDPRRRNILRSLRRNTKKPKPKPRPSITKATWESNYFGVPLTTVVTPEKP
  IPIFIERCIEYIEATGLSTEGIYRVSGNKSEMESLQRQFDQDHNLDLAEKDFTVNTVAGA
  MKSFFSELPDPLVPYNMQIDLVEAHKINDREQKLHALKEVLKKFPKENHEVFKYVISHLN
  KVSHNNKVNLMTSENLSICFWPTLMRPDFSTMDALTATRTYQTIIELFIQQCPFFFYNRP
  ITEPPGARPSSPSAVASTVPFLTSTPVTSQPSPPQSPPPTPQSPMQPLLPSQLQAEHTL
• Function: Rho GTPase-activating protein (GAP). Binds several acidic phospholipids which inhibits the Rho GAP activity to promote the Rac GAP activity. This binding is inhibited by phosphorylation by PRKCA. Involved in cell differentiation as well as cell adhesion and migration, plays an important role in retinal tissue morphogenesis, neural tube fusion, midline fusion of the cerebral hemispheres and mammary gland branching morphogenesis. Transduces signals from p21-ras to the nucleus, acting via the ras GTPase-activating protein (GAP). Transduces SRC-dependent signals from cell-surface adhesion molecules, such as laminin, to promote neurite outgrowth. Regulates axon outgrowth, guidance and fasciculation. Modulates Rho GTPase-dependent F-actin polymerization, organization and assembly, is involved in polarized cell migration and in the positive regulation of ciliogenesis and cilia elongation. During mammary gland development, is required in both the epithelial and stromal compartments for ductal outgrowth. Represses transcription of the glucocorticoid receptor by binding to the cis-acting regulatory sequence 5'-GAGAAAAGAAACTGGAGAAACTC-3'; this function is however unclear and would need additional experimental evidences.
• Tissue Specificity: Detected in neutrophils (at protein level).
• KEGG Pathway:
  Focal adhesion (hsa04510)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOG GTPase cycle (R-HSA-9013408)
  RHOJ GTPase cycle (R-HSA-9013409)
  RAC3 GTPase cycle (R-HSA-9013423)
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  RND1 GTPase cycle (R-HSA-9696273)
  Sema4D mediated inhibition of cell attachment and migration (R-HSA-416550)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[2]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[2]
Progressive non-fluent aphasia	DIS9HZET	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[5]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[5]
Glioma	DIS5RPEH	Limited	Genetic Variation	[7]

4 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 35 (ARHGAP35).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rho GTPase-activating protein 35 (ARHGAP35).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rho GTPase-activating protein 35 (ARHGAP35).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Rho GTPase-activating protein 35 (ARHGAP35).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[10]
Folic acid	DMEMBJC	Approved	Folic acid increases the activity of Rho GTPase-activating protein 35 (ARHGAP35).	[11]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Rho GTPase-activating protein 35 (ARHGAP35).	[18]

References

• [1] Growth inhibition of KRASand EGFRmutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis.Oncol Rep. 2018 Sep;40(3):1761-1768. doi: 10.3892/or.2018.6536. Epub 2018 Jul 2.
• [2] Glucocorticoid receptor DNA binding factor 1 expression and osteosarcoma prognosis.Tumour Biol. 2014 Dec;35(12):12449-58. doi: 10.1007/s13277-014-2563-z. Epub 2014 Sep 4.
• [3] Activated G(alpha)13 impairs cell invasiveness through p190RhoGAP-mediated inhibition of RhoA activity.Cancer Res. 2008 Oct 15;68(20):8221-30. doi: 10.1158/0008-5472.CAN-08-0561.
• [4] Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia.Brain. 2017 May 1;140(5):1437-1446. doi: 10.1093/brain/awx066.
• [5] p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity.J Cell Biol. 2018 Sep 3;217(9):3183-3201. doi: 10.1083/jcb.201710058. Epub 2018 Jun 22.
• [6] Ubiquitin ligase TRIM65 promotes colorectal cancer metastasis by targeting ARHGAP35 for protein degradation.Oncogene. 2019 Sep;38(37):6429-6444. doi: 10.1038/s41388-019-0891-6. Epub 2019 Jul 22.
• [7] p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3.Genes Dev. 2003 Feb 15;17(4):476-87. doi: 10.1101/gad.1040003.
• [8] 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.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 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.
• [11] Folic acid inhibits endothelial cell migration through inhibiting the RhoA activity mediated by activating the folic acid receptor/cSrc/p190RhoGAP-signaling pathway. Biochem Pharmacol. 2013 Feb 1;85(3):376-84. doi: 10.1016/j.bcp.2012.11.011. Epub 2012 Nov 23.
• [12] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.