Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR1QQA3)

• DOT Name: Rap guanine nucleotide exchange factor 6 (RAPGEF6)
• Synonyms: PDZ domain-containing guanine nucleotide exchange factor 2; PDZ-GEF2; RA-GEF-2
• Gene Name: RAPGEF6
• Related Disease:
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Schizophrenia
  Asthma
• UniProt ID: RPGF6_HUMAN
• PDB ID: 2D93; 3LNY
• Pfam ID: PF00027 ; PF00595 ; PF00788 ; PF00617 ; PF00618
• Sequence:
  MNSPVDPGARQALRKKPPERTPEDLNTIYSYLHGMEILSNLREHQLRLMSARARYERYSG
  NQVLFCSETIARCWYILLSGSVLVKGSMVLPPCSFGKQFGGKRGCDCLVLEPSEMIVVEN
  AKDNEDSILQREIPARQSRRRFRKINYKGERQTITDDVEVNSYLSLPADLTKMHLTENPH
  PQVTHVSSSQSGCSIASDSGSSSLSDIYQATESEVGDVDLTRLPEGPVDSEDDEEEDEEI
  DRTDPLQGRDLVRECLEKEPADKTDDDIEQLLEFMHQLPAFANMTMSVRRELCSVMIFEV
  VEQAGAIILEDGQELDSWYVILNGTVEISHPDGKVENLFMGNSFGITPTLDKQYMHGIVR
  TKVDDCQFVCIAQQDYWRILNHVEKNTHKVEEEGEIVMVHEHRELDRSGTRKGHIVIKAT
  PERLIMHLIEEHSIVDPTYIEDFLLTYRTFLESPLDVGIKLLEWFKIDSLRDKVTRIVLL
  WVNNHFNDFEGDPAMTRFLEEFEKNLEDTKMNGHLRLLNIACAAKAKWRQVVLQKASRES
  PLQFSLNGGSEKGFGIFVEGVEPGSKAADSGLKRGDQIMEVNGQNFENITFMKAVEILRN
  NTHLALTVKTNIFVFKELLFRTEQEKSGVPHIPKIAEKKSNRHSIQHVPGDIEQTSQEKG
  SKKVKANTVSGGRNKIRKILDKTRFSILPPKLFSDGGLSQSQDDSIVGTRHCRHSLAIMP
  IPGTLSSSSPDLLQPTTSMLDFSNPSDIPDQVIRVFKVDQQSCYIIISKDTTAKEVVFHA
  VHEFGLTGASDTYSLCEVSVTPEGVIKQRRLPDQFSKLADRIQLNGRYYLKNNMETETLC
  SDEDAQELVKESQLSMLQLSTIEVATQLSMRDFDLFRNIEPTEYIDDLFKLNSKTGNTHL
  KRFEDIVNQETFWVASEILTEANQLKRMKIIKHFIKIALHCRECKNFNSMFAIISGLNLA
  SVARLRGTWEKLPSKYEKHLQDLQDIFDPSRNMAKYRNILSSQSMQPPIIPLFPVVKKDM
  TFLHEGNDSKVDGLVNFEKLRMISKEIRQVVRMTSANMDPAMMFRQRSLSQGSTNSNMLD
  VQGGAHKKRARRSSLLNAKKLYEDAQMARKVKQYLSSLDVETDEEKFQMMSLQWEPAYGT
  LTKNLSEKRSAKSSEMSPVPMRSAGQTTKAHLHQPHRVSQVLQVPAVNLHPIRKKGQTKD
  PALNTSLPQKVLGTTEEISGKKHTEDTISVASSLHSSPPASPQGSPHKGYTLIPSAKSDN
  LSDSSHSEISSRSSIVSNCSVDSMSAALQDERCSSQALAVPESTGALEKTEHASGIGDHS
  QHGPGWTLLKPSLIKCLAVSSSVSNEEISQEHIIIEAADSGRGSWTSCSSSSHDNFQSLP
  NPKSWDFLNSYRHTHLDDPIAEVEPTDSEPYSCSKSCSRTCGQCKGSLERKSWTSSSSLS
  DTYEPNYGTVKQRVLESTPAESSEGLDPKDATDPVYKTVTSSTEKGLIVYCVTSPKKDDR
  YREPPPTPPGYLGISLADLKEGPHTHLKPPDYSVAVQRSKMMHNSLSRLPPASLSSNLVA
  CVPSKIVTQPQRHNLQPFHPKLGDVTDADSEADENEQVSAV
• Function: Guanine nucleotide exchange factor (GEF) for Rap1A, Rap2A and M-Ras GTPases. Does not interact with cAMP.
• Tissue Specificity: Isoform 3 has highest expression levels in the brain, heart, liver, lung and placenta and is barely detectable in skeletal muscle, kidney and pancreas.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Tight junction (hsa04530)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Asthma	DISW9QNS	moderate	Genetic Variation	[4]

10 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 Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[10]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[15]

4 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 Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Rap guanine nucleotide exchange factor 6 (RAPGEF6).	[9]

References

• [1] A novel Alzheimer disease locus located near the gene encoding tau protein.Mol Psychiatry. 2016 Jan;21(1):108-17. doi: 10.1038/mp.2015.23. Epub 2015 Mar 17.
• [2] Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase.Breast Cancer Res. 2011 Mar 23;13(2):R31. doi: 10.1186/bcr2853.
• [3] Rapgef2, a guanine nucleotide exchange factor for Rap1 small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression.Biochem Biophys Res Commun. 2017 Nov 4;493(1):139-145. doi: 10.1016/j.bbrc.2017.09.062. Epub 2017 Sep 14.
• [4] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [9] 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.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [12] 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.
• [13] 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.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.