Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUWZTH7)

• DOT Name: Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3)
• Synonyms: Centaurin-delta-3; Cnt-d3
• Gene Name: ARAP3
• Related Disease:
  Neoplasm
  Advanced cancer
  Alzheimer disease
  Anthrax
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  HIV infectious disease
  B-cell lymphoma
  Cervical cancer
  Cervical carcinoma
• UniProt ID: ARAP3_HUMAN
• PDB ID: 2KG5; 2LNW; 5JCP; 5JD0; 7A9B; 7YIR; 7YIS
• Pfam ID: PF01412 ; PF00169 ; PF00788 ; PF00620 ; PF07647
• Sequence:
  MAAPQDLDIAVWLATVHLEQYADTFRRHGLATAGAARGLGHEELKQLGISATGHRKRILR
  LLQTGTEEGSLDPKSDSAMEPSPSPAPQAQPPKPVPKPRTVFGGLSGPATTQRPGLSPAL
  GGPGVSRSPEPSPRPPPLPTSSSEQSSALNTVEMMPNSIYFGLDSRGRAQAAQDKAPDSS
  QISAPTPALRPTTGTVHIMDPGCLYYGVQPVGTPGAPDRRESRGVCQGRAEHRLSRQDLE
  AREDAGYASLELPGDSTLLSPTLETEETSDDLISPYASFSFTADRLTPLLSGWLDKLSPQ
  GNYVFQRRFVQFNGRSLMYFGSDKDPFPKGVIPLTAIEMTRSSKDNKFQVITGQRVFVFR
  TESEAQRDMWCSTLQSCLKEQRLLGHPRPPQPPRPLRTGMLELRGHKAKVFAALSPGELA
  LYKSEQAFSLGIGICFIELQGCSVRETKSRSFDLLTPHRCFSFTAESGGARQSWAAALQE
  AVTETLSDYEVAEKIWSNRANRQCADCGSSRPDWAAVNLGVVICKQCAGQHRALGSGISK
  VQSLKLDTSVWSNEIVQLFIVLGNDRANRFWAGTLPPGEGLHPDATPGPRGEFISRKYRL
  GLFRKPHPQYPDHSQLLQALCAAVARPNLLKNMTQLLCVEAFEGEEPWFPPAPDGSCPGL
  LPSDPSPGVYNEVVVRATYSGFLYCSPVSNKAGPSPPRRGRDAPPRLWCVLGAALEMFAS
  ENSPEPLSLIQPQDIVCLGVSPPPTDPGDRFPFSFELILAGGRIQHFGTDGADSLEAWTS
  AVGKWFSPLSCHQLLGPGLLRLGRLWLRSPSHTAPAPGLWLSGFGLLRGDHLFLCSAPGP
  GPPAPEDMVHLRRLQEISVVSAADTPDKKEHLVLVETGRTLYLQGEGRLDFTAWNAAIGG
  AAGGGGTGLQEQQMSRGDIPIIVDACISFVTQHGLRLEGVYRKGGARARSLRLLAEFRRD
  ARSVKLRPGEHFVEDVTDTLKRFFRELDDPVTSARLLPRWREAAELPQKNQRLEKYKDVI
  GCLPRVNRRTLATLIGHLYRVQKCAALNQMCTRNLALLFAPSVFQTDGRGEHEVRVLQEL
  IDGYISVFDIDSDQVAQIDLEVSLITTWKDVQLSQAGDLIMEVYIEQQLPDNCVTLKVSP
  TLTAEELTNQVLEMRGTAAGMDLWVTFEIREHGELERPLHPKEKVLEQALQWCQLPEPCS
  ASLLLKKVPLAQAGCLFTGIRRESPRVGLLRCREEPPRLLGSRFQERFFLLRGRCLLLLK
  EKKSSKPEREWPLEGAKVYLGIRKKLKPPTPWGFTLILEKMHLYLSCTDEDEMWDWTTSI
  LKAQHDDQQPVVLRRHSSSDLARQKFGTMPLLPIRGDDSGATLLSANQTLRRLHNRRTLS
  MFFPMKSSQGSVEEQEELEEPVYEEPVYEEVGAFPELIQDTSTSFSTTREWTVKPENPLT
  SQKSLDQPFLSKSSTLGQEERPPEPPPGPPSKSSPQARGSLEEQLLQELSSLILRKGETT
  AGLGSPSQPSSPQSPSPTGLPTQTPGFPTQPPCTSSPPSSQPLT
• Function: Phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein that modulates actin cytoskeleton remodeling by regulating ARF and RHO family members. Is activated by phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) binding. Can be activated by phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding, albeit with lower efficiency. Acts on ARF6, RAC1, RHOA and CDC42. Plays a role in the internalization of anthrax toxin.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Endocytosis (hsa04144)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Anthrax	DISFPT78	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
B-cell lymphoma	DISIH1YQ	moderate	Genetic Variation	[7]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[8]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Arf-GAP with Rho-GAP domain, ANK repeat and PH domain-containing protein 3 (ARAP3).	[16]

References

• [1] Whole genome sequence analysis suggests intratumoral heterogeneity in dissemination of breast cancer to lymph nodes.PLoS One. 2014 Dec 29;9(12):e115346. doi: 10.1371/journal.pone.0115346. eCollection 2014.
• [2] ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion.Oncogene. 2011 Mar 24;30(12):1413-21. doi: 10.1038/onc.2010.522. Epub 2010 Nov 15.
• [3] A modulates actin cytoskeleton via SHIP2-mediated phosphoinositide metabolism.Sci Rep. 2019 Oct 29;9(1):15557. doi: 10.1038/s41598-019-51914-2.
• [4] EST-based genome-wide gene inactivation identifies ARAP3 as a host protein affecting cellular susceptibility to anthrax toxin.Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17246-51. doi: 10.1073/pnas.0407794101. Epub 2004 Nov 29.
• [5] Bioinformatic analysis of prognostic value of ARAP3 in breast cancer and the associated signaling pathways.Eur Rev Med Pharmacol Sci. 2017 May;21(10):2405-2412.
• [6] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [7] Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma.Nat Genet. 2014 Nov;46(11):1233-8. doi: 10.1038/ng.3105. Epub 2014 Sep 28.
• [8] Gene dosage alterations revealed by cDNA microarray analysis in cervical cancer: identification of candidate amplified and overexpressed genes.Genes Chromosomes Cancer. 2007 Apr;46(4):373-84. doi: 10.1002/gcc.20418.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.