Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZWX2AA)

• DOT Name: Rap guanine nucleotide exchange factor 2 (RAPGEF2)
• Synonyms: Cyclic nucleotide ras GEF; CNrasGEF; Neural RAP guanine nucleotide exchange protein; nRap GEP; PDZ domain-containing guanine nucleotide exchange factor 1; PDZ-GEF1; RA-GEF-1; Ras/Rap1-associating GEF-1
• Gene Name: RAPGEF2
• Related Disease:
  Benign adult familial myoclonic epilepsy
  Dravet syndrome
  Epilepsy
  Familial infantile myoclonic epilepsy
  Myoclonic-astatic epilepsy
  Schizophrenia
  Subcortical band heterotopia
  Amyotrophic lateral sclerosis
  Epilepsy, familial adult myoclonic, 7
  Familial nephrotic syndrome
  Glomerulosclerosis
• UniProt ID: RPGF2_HUMAN
• PDB ID: 6QDT
• Pfam ID: PF00595 ; PF00788 ; PF00617 ; PF00618
• Sequence:
  MKPLAIPANHGVMGQQEKHSLPADFTKLHLTDSLHPQVTHVSSSHSGCSITSDSGSSSLS
  DIYQATESEAGDMDLSGLPETAVDSEDDDDEEDIERASDPLMSRDIVRDCLEKDPIDRTD
  DDIEQLLEFMHQLPAFANMTMSVRRELCAVMVFAVVERAGTIVLNDGEELDSWSVILNGS
  VEVTYPDGKAEILCMGNSFGVSPTMDKEYMKGVMRTKVDDCQFVCIAQQDYCRILNQVEK
  NMQKVEEEGEIVMVKEHRELDRTGTRKGHIVIKGTSERLTMHLVEEHSVVDPTFIEDFLL
  TYRTFLSSPMEVGKKLLEWFNDPSLRDKVTRVVLLWVNNHFNDFEGDPAMTRFLEEFENN
  LEREKMGGHLRLLNIACAAKAKRRLMTLTKPSREAPLPFILLGGSEKGFGIFVDSVDSGS
  KATEAGLKRGDQILEVNGQNFENIQLSKAMEILRNNTHLSITVKTNLFVFKELLTRLSEE
  KRNGAPHLPKIGDIKKASRYSIPDLAVDVEQVIGLEKVNKKSKANTVGGRNKLKKILDKT
  RISILPQKPYNDIGIGQSQDDSIVGLRQTKHIPTALPVSGTLSSSNPDLLQSHHRILDFS
  ATPDLPDQVLRVFKADQQSRYIMISKDTTAKEVVIQAIREFAVTATPDQYSLCEVSVTPE
  GVIKQRRLPDQLSKLADRIQLSGRYYLKNNMETETLCSDEDAQELLRESQISLLQLSTVE
  VATQLSMRNFELFRNIEPTEYIDDLFKLRSKTSCANLKRFEEVINQETFWVASEILRETN
  QLKRMKIIKHFIKIALHCRECKNFNSMFAIISGLNLAPVARLRTTWEKLPNKYEKLFQDL
  QDLFDPSRNMAKYRNVLNSQNLQPPIIPLFPVIKKDLTFLHEGNDSKVDGLVNFEKLRMI
  AKEIRHVGRMASVNMDPALMFRTRKKKWRSLGSLSQGSTNATVLDVAQTGGHKKRVRRSS
  FLNAKKLYEDAQMARKVKQYLSNLELEMDEESLQTLSLQCEPATNTLPKNPGDKKPVKSE
  TSPVAPRAGSQQKAQSLPQPQQQPPPAHKINQGLQVPAVSLYPSRKKVPVKDLPPFGINS
  PQALKKILSLSEEGSLERHKKQAEDTISNASSQLSSPPTSPQSSPRKGYTLAPSGTVDNF
  SDSGHSEISSRSSIVSNSSFDSVPVSLHDERRQRHSVSIVETNLGMGRMERRTMIEPDQY
  SLGSYAPMSEGRGLYATATVISSPSTEELSQDQGDRASLDAADSGRGSWTSCSSGSHDNI
  QTIQHQRSWETLPFGHTHFDYSGDPAGLWASSSHMDQIMFSDHSTKYNRQNQSRESLEQA
  QSRASWASSTGYWGEDSEGDTGTIKRRGGKDVSIEAESSSLTSVTTEETKPVPMPAHIAV
  ASSTTKGLIARKEGRYREPPPTPPGYIGIPITDFPEGHSHPARKPPDYNVALQRSRMVAR
  SSDTAGPSSVQQPHGHPTSSRPVNKPQWHKPNESDPRLAPYQSQGFSTEEDEDEQVSAV
• Function: Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner. Serves as a link between cell surface receptors and Rap/Ras GTPases in intracellular signaling cascades. Acts also as an effector for Rap1 by direct association with Rap1-GTP thereby leading to the amplification of Rap1-mediated signaling. Shows weak activity on HRAS. It is controversial whether RAPGEF2 binds cAMP and cGMP or not. Its binding to ligand-activated beta-1 adrenergic receptor ADRB1 leads to the Ras activation through the G(s)-alpha signaling pathway. Involved in the cAMP-induced Ras and Erk1/2 signaling pathway that leads to sustained inhibition of long term melanogenesis by reducing dendrite extension and melanin synthesis. Provides also inhibitory signals for cell proliferation of melanoma cells and promotes their apoptosis in a cAMP-independent nanner. Regulates cAMP-induced neuritogenesis by mediating the Rap1/B-Raf/ERK signaling through a pathway that is independent on both PKA and RAPGEF3/RAPGEF4. Involved in neuron migration and in the formation of the major forebrain fiber connections forming the corpus callosum, the anterior commissure and the hippocampal commissure during brain development. Involved in neuronal growth factor (NGF)-induced sustained activation of Rap1 at late endosomes and in brain-derived neurotrophic factor (BDNF)-induced axon outgrowth of hippocampal neurons. Plays a role in the regulation of embryonic blood vessel formation and in the establishment of basal junction integrity and endothelial barrier function. May be involved in the regulation of the vascular endothelial growth factor receptor KDR and cadherin CDH5 expression at allantois endothelial cell-cell junctions.
• Tissue Specificity: Expressed in primary neuronal and endocrine cells (at protein level). Highest expression levels in brain. Lower expression levels in heart, kidney, lung, placenta and blood leukocytes.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Rap1 sig.ling pathway (hsa04015)
  Tight junction (hsa04530)
• Reactome Pathway: RAF/MAP kinase cascade (R-HSA-5673001)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Benign adult familial myoclonic epilepsy	DISIMWOV	Strong	Biomarker	[1]
Dravet syndrome	DISJF7LY	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Familial infantile myoclonic epilepsy	DISELJ0F	Strong	Biomarker	[1]
Myoclonic-astatic epilepsy	DISTAVMU	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Subcortical band heterotopia	DISHN7JS	moderate	Biomarker	[4]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Autosomal dominant	[5]
Epilepsy, familial adult myoclonic, 7	DISWUKG9	Limited	Autosomal dominant	[1]
Familial nephrotic syndrome	DISADF8G	Limited	Genetic Variation	[6]
Glomerulosclerosis	DISJF20Z	Limited	Genetic Variation	[6]

5 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 Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[15]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[19]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[20]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[22]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Rap guanine nucleotide exchange factor 2 (RAPGEF2).	[23]

References

• [1] Expansions?of?intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet. 2018 Apr;50(4):581-590. doi: 10.1038/s41588-018-0067-2. Epub 2018 Mar 5.
• [2] Intronic (TTTGA)(n) insertion in SAMD12 also causes familial cortical myoclonic tremor with epilepsy.Mov Disord. 2019 Oct;34(10):1571-1576. doi: 10.1002/mds.27832. Epub 2019 Sep 4.
• [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] Comprehensive behavioral analysis of mice deficient in Rapgef2 and Rapgef6, a subfamily of guanine nucleotide exchange factors for Rap small GTPases possessing the Ras/Rap-associating domain.Mol Brain. 2018 May 10;11(1):27. doi: 10.1186/s13041-018-0370-y.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] Disruption of MAGI2-RapGEF2-Rap1 signaling contributes to podocyte dysfunction in congenital nephrotic syndrome caused by mutations in MAGI2.Kidney Int. 2019 Sep;96(3):642-655. doi: 10.1016/j.kint.2019.03.016. Epub 2019 Mar 28.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [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] 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.
• [16] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.
• [21] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
• [22] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.
• [23] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.