Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMOW4Z4)

• DOT Name: Rap guanine nucleotide exchange factor 3 (RAPGEF3)
• Synonyms: Exchange factor directly activated by cAMP 1; Exchange protein directly activated by cAMP 1; EPAC 1; Rap1 guanine-nucleotide-exchange factor directly activated by cAMP; cAMP-regulated guanine nucleotide exchange factor I; cAMP-GEFI
• Gene Name: RAPGEF3
• UniProt ID: RPGF3_HUMAN
• PDB ID: 6H7E
• Pfam ID: PF00027 ; PF00610 ; PF00617 ; PF00618
• Sequence:
  MKVGWPGESCWQVGLAVEDSPALGAPRVGALPDVVPEGTLLNMVLRRMHRPRSCSYQLLL
  EHQRPSCIQGLRWTPLTNSEESLDFSESLEQASTERVLRAGRQLHRHLLATCPNLIRDRK
  YHLRLYRQCCSGRELVDGILALGLGVHSRSQVVGICQVLLDEGALCHVKHDWAFQDRDAQ
  FYRFPGPEPEPVRTHEMEEELAEAVALLSQRGPDALLTVALRKPPGQRTDEELDLIFEEL
  LHIKAVAHLSNSVKRELAAVLLFEPHSKAGTVLFSQGDKGTSWYIIWKGSVNVVTHGKGL
  VTTLHEGDDFGQLALVNDAPRAATIILREDNCHFLRVDKQDFNRIIKDVEAKTMRLEEHG
  KVVLVLERASQGAGPSRPPTPGRNRYTVMSGTPEKILELLLEAMGPDSSAHDPTETFLSD
  FLLTHRVFMPSAQLCAALLHHFHVEPAGGSEQERSTYVCNKRQQILRLVSQWVALYGSML
  HTDPVATSFLQKLSDLVGRDTRLSNLLREQWPERRRCHRLENGCGNASPQMKARNLPVWL
  PNQDEPLPGSSCAIQVGDKVPYDICRPDHSVLTLQLPVTASVREVMAALAQEDGWTKGQV
  LVKVNSAGDAIGLQPDARGVATSLGLNERLFVVNPQEVHELIPHPDQLGPTVGSAEGLDL
  VSAKDLAGQLTDHDWSLFNSIHQVELIHYVLGPQHLRDVTTANLERFMRRFNELQYWVAT
  ELCLCPVPGPRAQLLRKFIKLAAHLKEQKNLNSFFAVMFGLSNSAISRLAHTWERLPHKV
  RKLYSALERLLDPSWNHRVYRLALAKLSPPVIPFMPLLLKDMTFIHEGNHTLVENLINFE
  KMRMMARAARMLHHCRSHNPVPLSPLRSRVSHLHEDSQVARISTCSEQSLSTRSPASTWA
  YVQQLKVIDNQRELSRLSRELEP
• Function: Guanine nucleotide exchange factor (GEF) for RAP1A and RAP2A small GTPases that is activated by binding cAMP. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which it activates the PI3K gamma complex and which is involved in angiogenesis. Plays a role in the modulation of the cAMP-induced dynamic control of endothelial barrier function through a pathway that is independent on Rho-mediated signaling. Required for the actin rearrangement at cell-cell junctions, such as stress fibers and junctional actin.
• Tissue Specificity: Widely expressed with highest levels in adult kidney, heart, thyroid and brain, and fetal kidney.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Phospholipase D sig.ling pathway (hsa04072)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Leukocyte transendothelial migration (hsa04670)
  Long-term potentiation (hsa04720)
  Serotonergic sy.pse (hsa04726)
• Reactome Pathway:
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Rap1 signalling (R-HSA-392517)
  Regulation of insulin secretion (R-HSA-422356)
  Integrin signaling (R-HSA-354192)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[4]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[5]
Hydrocortisone	DMGEMB7	Approved	Hydrocortisone increases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[6]
Levodopa	DMN3E57	Approved	Levodopa increases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein affects the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Rap guanine nucleotide exchange factor 3 (RAPGEF3).	[11]

References

• [1] 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.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] 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.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [6] Hydrocortisone enhances the barrier properties of HBMEC/ci, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects. Fluids Barriers CNS. 2015 Mar 5;12:7. doi: 10.1186/s12987-015-0003-0. eCollection 2015.
• [7] Multiple treatments with L-3,4-dihydroxyphenylalanine modulate dopamine biosynthesis and neurotoxicity through the protein kinase A-transient extracellular signal-regulated kinase and exchange protein activation by cyclic AMP-sustained extracellular signal-regulated kinase signaling pathways. J Neurosci Res. 2014 Dec;92(12):1746-56. doi: 10.1002/jnr.23450. Epub 2014 Jul 12.
• [8] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [9] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [10] 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.
• [11] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.