Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT59PSSE)

DOT Name Rap guanine nucleotide exchange factor 4 (RAPGEF4)
Synonyms Exchange factor directly activated by cAMP 2; Exchange protein directly activated by cAMP 2; EPAC 2; cAMP-regulated guanine nucleotide exchange factor II; cAMP-GEFII
Gene Name RAPGEF4
Related Disease
Prostate cancer ( )
UniProt ID
RPGF4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF00027 ; PF00610 ; PF00617 ; PF00618
Sequence
MVAAHAAHSSSSAEWIACLDKRPLERSSEDVDIIFTRLKEVKAFEKFHPNLLHQICLCGY
YENLEKGITLFRQGDIGTNWYAVLAGSLDVKVSETSSHQDAVTICTLGIGTAFGESILDN
TPRHATIVTRESSELLRIEQKDFKALWEKYRQYMAGLLAPPYGVMETGSNNDRIPDKENT
PLIEPHVPLRPANTITKVPSEKILRAGKILRNAILSRAPHMIRDRKYHLKTYRQCCVGTE
LVDWMMQQTPCVHSRTQAVGMWQVLLEDGVLNHVDQEHHFQDKYLFYRFLDDEHEDAPLP
TEEEKKECDEELQDTMLLLSQMGPDAHMRMILRKPPGQRTVDDLEIIYEELLHIKALSHL
STTVKRELAGVLIFESHAKGGTVLFNQGEEGTSWYIILKGSVNVVIYGKGVVCTLHEGDD
FGKLALVNDAPRAASIVLREDNCHFLRVDKEDFNRILRDVEANTVRLKEHDQDVLVLEKV
PAGNRASNQGNSQPQQKYTVMSGTPEKILEHFLETIRLEATLNEATDSVLNDFIMMHCVF
MPNTQLCPALVAHYHAQPSQGTEQEKMDYALNNKRRVIRLVLQWAAMYGDLLQEDDVSMA
FLEEFYVSVSDDARMIAALKEQLPELEKIVKQISEDAKAPQKKHKVLLQQFNTGDERAQK
RQPIRGSDEVLFKVYCMDHTYTTIRVPVATSVKEVISAVADKLGSGEGLIIVKMSSGGEK
VVLKPNDVSVFTTLTINGRLFACPREQFDSLTPLPEQEGPTVGTVGTFELMSSKDLAYQM
TIYDWELFNCVHELELIYHTFGRHNFKKTTANLDLFLRRFNEIQFWVVTEICLCSQLSKR
VQLLKKFIKIAAHCKEYKNLNSFFAIVMGLSNVAVSRLALTWEKLPSKFKKFYAEFESLM
DPSRNHRAYRLTVAKLEPPLIPFMPLLIKDMTFTHEGNKTFIDNLVNFEKMRMIANTART
VRYYRSQPFNPDAAQANKNHQDVRSYVRQLNVIDNQRTLSQMSHRLEPRRP
Function
Guanine nucleotide exchange factor (GEF) for RAP1A, RAP1B and RAP2A small GTPases that is activated by binding cAMP. Seems not to activate RAB3A. Involved in cAMP-dependent, PKA-independent exocytosis through interaction with RIMS2.
Tissue Specificity Predominantly expressed in brain and adrenal gland. Isoform 2 is expressed in liver. Isoform 1 is expressed in liver at very low levels.
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 )
Insulin secretion (hsa04911 )
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 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Prostate cancer DISF190Y Limited Autosomal dominant [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
12 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 4 (RAPGEF4). [2]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [3]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [4]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [5]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [2]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [6]
Clorgyline DMCEUJD Approved Clorgyline increases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [7]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [8]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [9]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [10]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [11]
3R14S-OCHRATOXIN A DM2KEW6 Investigative 3R14S-OCHRATOXIN A increases the expression of Rap guanine nucleotide exchange factor 4 (RAPGEF4). [8]
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⏷ Show the Full List of 12 Drug(s)

References

1 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.
2 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
3 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.
4 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
5 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.
6 Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
7 Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
8 Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
9 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
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 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.