Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7162TD)

• DOT Name: Rho guanine nucleotide exchange factor 25 (ARHGEF25)
• Synonyms: Guanine nucleotide exchange factor GEFT; Rac/Cdc42/Rho exchange factor GEFT; RhoA/Rac/Cdc42 guanine nucleotide exchange factor GEFT; p63RhoGEF
• Gene Name: ARHGEF25
• Related Disease:
  Advanced cancer
  Bartter syndrome
  Colorectal carcinoma
  High blood pressure
  Rhabdomyosarcoma
  Gitelman syndrome
• UniProt ID: ARHGP_HUMAN
• PDB ID: 2RGN
• Pfam ID: PF00621
• Sequence:
  MRGGHKGGRCACPRVIRKVLAKCGCCFARGGRESYSIAGSEGSISASAASGLAAPSGPSS
  GLSSGPCSPGPPGPVSGLRRWLDHSKHCLSVETEADSGQAGPYENWMLEPALATGEELPE
  LTLLTTLLEGPGDKTQPPEEETLSQAPESEEEQKKKALERSMYVLSELVETEKMYVDDLG
  QIVEGYMATMAAQGVPESLRGRDRIVFGNIQQIYEWHRDYFLQELQRCLKDPDWLAQLFI
  KHERRLHMYVVYCQNKPKSEHVVSEFGDSYFEELRQQLGHRLQLNDLLIKPVQRIMKYQL
  LLKDFLKYYNRAGMDTADLEQAVEVMCFVPKRCNDMMTLGRLRGFEGKLTAQGKLLGQDT
  FWVTEPEAGGLLSSRGRERRVFLFEQIIIFSEALGGGVRGGTQPGYVYKNSIKVSCLGLE
  GNLQGDPCRFALTSRGPEGGIQRYVLQAADPAISQAWIKHVAQILESQRDFLNALQSPIE
  YQRRESQTNSLGRPRGPGVGSPGRIQLGDQAQGSTHTPINGSLPSLLLSPKGEVARALLP
  LDKQALGDIPQAPHDSPPVSPTPKTPPCQARLAKLDEDEL
• Function: May play a role in actin cytoskeleton reorganization in different tissues since its activation induces formation of actin stress fibers. It works as a guanine nucleotide exchange factor for Rho family of small GTPases. Links specifically G alpha q/11-coupled receptors to RHOA activation. May be an important regulator of processes involved in axon and dendrite formation. In neurons seems to be an exchange factor primarily for RAC1. Involved in skeletal myogenesis.
• Tissue Specificity: Isoform 1 and isoform 2 are highly expressed in excitable tissues, such as brain, heart and muscle. Also detected in kidney and liver.
• Reactome Pathway:
  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)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Bartter syndrome	DIS7D44B	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
High blood pressure	DISY2OHH	Strong	Altered Expression	[3]
Rhabdomyosarcoma	DISNR7MS	moderate	Posttranslational Modification	[4]
Gitelman syndrome	DISEM9V2	Limited	Genetic Variation	[3]

3 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 Rho guanine nucleotide exchange factor 25 (ARHGEF25).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho guanine nucleotide exchange factor 25 (ARHGEF25).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Rho guanine nucleotide exchange factor 25 (ARHGEF25).	[11]

4 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 guanine nucleotide exchange factor 25 (ARHGEF25).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho guanine nucleotide exchange factor 25 (ARHGEF25).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rho guanine nucleotide exchange factor 25 (ARHGEF25).	[8]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of Rho guanine nucleotide exchange factor 25 (ARHGEF25).	[10]

References

• [1] GEFT protein expression in digestive tract malignant tumors and its clinical significance.Oncol Lett. 2019 Nov;18(5):5577-5590. doi: 10.3892/ol.2019.10915. Epub 2019 Sep 24.
• [2] Increased level of p63RhoGEF and RhoA/Rho kinase activity in hypertensive patients.J Hypertens. 2014 Feb;32(2):331-8. doi: 10.1097/HJH.0000000000000075.
• [3] Gq/p63RhoGEF interaction in RhoA/Rho kinase signaling: investigation in Gitelman's syndrome and implications with hypertension.J Endocrinol Invest. 2018 Mar;41(3):351-356. doi: 10.1007/s40618-017-0749-0. Epub 2017 Aug 24.
• [4] Epigenetically upregulated GEFT-derived invasion and metastasis of rhabdomyosarcoma via epithelial mesenchymal transition promoted by the Rac1/Cdc42-PAK signalling pathway.EBioMedicine. 2019 Dec;50:122-134. doi: 10.1016/j.ebiom.2019.10.060. Epub 2019 Nov 21.
• [5] 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.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [11] 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.