Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ0TBN1)

DOT Name Rap guanine nucleotide exchange factor 1 (RAPGEF1)
Synonyms CRK SH3-binding GNRP; Guanine nucleotide-releasing factor 2; Protein C3G
Gene Name RAPGEF1
Related Disease
Advanced cancer ( )
Colon cancer ( )
Gastric cancer ( )
Lung cancer ( )
Ovarian cancer ( )
Squamous cell carcinoma ( )
Neuroblastoma ( )
Non-insulin dependent diabetes ( )
UniProt ID
RPGF1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5L23
Pfam ID
PF00617 ; PF00618
Sequence
MDTDSQRSHLSSFTMKLMDKFHSPKIKRTPSKKGKPAEVSVKIPEKPVNKEATDRFLPEG
YPLPLDLEQQAVEFMSTSAVASRSQRQKNLSWLEEKEKEVVSALRYFKTIVDKMAIDKKV
LEMLPGSASKVLEAILPLVQNDPRIQHSSALSSCYSRVYQSLANLIRWSDQVMLEGVNSE
DKEMVTTVKGVIKAVLDGVKELVRLTIEKQGRPSPTSPVKPSSPASKPDGPAELPLTDRE
VEILNKTTGMSQSTELLPDATDEEVAPPKPPLPGIRVVDNSPPPALPPKKRQSAPSPTRV
AVVAPMSRATSGSSLPVGINRQDFDVDCYAQRRLSGGSHSYGGESPRLSPCSSIGKLSKS
DEQLSSLDRDSGQCSRNTSCETLDHYDPDYEFLQQDLSNADQIPQQTAWNLSPLPESLGE
SGSPFLGPPFQLPLGGHPQPDGPLAPGQQTDTPPALPEKKRRSAASQTADGSGCRVSYER
HPSQYDNISGEDLQSTAPIPSVPYAPFAAILPFQHGGSSAPVEFVGDFTAPESTGDPEKP
PPLPEKKNKHMLAYMQLLEDYSEPQPSMFYQTPQNEHIYQQKNKLLMEVYGFSDSFSGVD
SVQELAPPPALPPKQRQLEPPAGKDGHPRDPSAVSGVPGKDSRDGSERAPKSPDALESAQ
SEEEVDELSLIDHNEIMSRLTLKQEGDDGPDVRGGSGDILLVHATETDRKDLVLYCEAFL
TTYRTFISPEELIKKLQYRYEKFSPFADTFKKRVSKNTFFVLVRVVDELCLVELTEEILK
LLMELVFRLVCNGELSLARVLRKNILDKVDQKKLLRCATSSQPLAARGVAARPGTLHDFH
SHEIAEQLTLLDAELFYKIEIPEVLLWAKEQNEEKSPNLTQFTEHFNNMSYWVRSIIMLQ
EKAQDRERLLLKFIKIMKHLRKLNNFNSYLAILSALDSAPIRRLEWQKQTSEGLAEYCTL
IDSSSSFRAYRAALSEVEPPCIPYLGLILQDLTFVHLGNPDYIDGKVNFSKRWQQFNILD
SMRCFQQAHYDMRRNDDIINFFNDFSDHLAEEALWELSLKIKPRNITRRKTDREEKT
Function
Guanine nucleotide-releasing protein that binds to SH3 domain of CRK and GRB2/ASH. Transduces signals from CRK to activate RAS. Involved in cell branching and adhesion mediated by BCAR1-CRK-RAPGEF1 signaling and activation of RAP1. Plays a role in the establishment of basal endothelial barrier function. Plays a role in nerve growth factor (NGF)-induced sustained activation of Rap1 and neurite outgrowth.
Tissue Specificity Ubiquitously expressed in adult and fetus. Expression is high in adult skeletal muscle and placenta and in fetal brain and heart. Low levels of expression in adult and fetal liver.
KEGG Pathway
Rap1 sig.ling pathway (hsa04015 )
Focal adhesion (hsa04510 )
Neurotrophin sig.ling pathway (hsa04722 )
Insulin sig.ling pathway (hsa04910 )
Re.l cell carcinoma (hsa05211 )
Reactome Pathway
Downstream signal transduction (R-HSA-186763 )
MET activates RAP1 and RAC1 (R-HSA-8875555 )
RAC3 GTPase cycle (R-HSA-9013423 )
Erythropoietin activates RAS (R-HSA-9027284 )
Regulation of signaling by CBL (R-HSA-912631 )
Frs2-mediated activation (R-HSA-170968 )

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Biomarker [1]
Colon cancer DISVC52G Strong Genetic Variation [1]
Gastric cancer DISXGOUK Strong Genetic Variation [1]
Lung cancer DISCM4YA Strong Altered Expression [1]
Ovarian cancer DISZJHAP Strong Posttranslational Modification [1]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [2]
Neuroblastoma DISVZBI4 Limited Biomarker [3]
Non-insulin dependent diabetes DISK1O5Z Limited Genetic Variation [4]
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⏷ Show the Full List of 8 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
9 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [5]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [6]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [7]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [8]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [9]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [10]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [12]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [14]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE DMNQL17 Investigative 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [16]
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⏷ Show the Full List of 9 Drug(s)
3 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 1 (RAPGEF1). [11]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [13]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Rap guanine nucleotide exchange factor 1 (RAPGEF1). [15]
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References

1 Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer.Int J Oncol. 2011 Jun;38(6):1575-7. doi: 10.3892/ijo.2011.972. Epub 2011 Mar 11.
2 Inactivation of Crk SH3 domain-binding guanine nucleotide-releasing factor (C3G) in cervical squamous cell carcinoma.Int J Gynecol Cancer. 2006 Mar-Apr;16(2):763-71. doi: 10.1111/j.1525-1438.2006.00352.x.
3 Cytoskeletal remodeling by C3G to induce neurite-like extensions and inhibit motility in highly invasive breast carcinoma cells.Biochim Biophys Acta. 2011 Mar;1813(3):456-65. doi: 10.1016/j.bbamcr.2011.01.004. Epub 2011 Jan 9.
4 Association between polymorphisms in RAPGEF1, TP53, NRF1 and type 2 diabetes in Chinese Han population.Diabetes Res Clin Pract. 2011 Feb;91(2):171-6. doi: 10.1016/j.diabres.2010.11.019. Epub 2010 Dec 13.
5 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
6 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.
7 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
8 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
9 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.
10 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
11 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.
12 The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
13 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.
14 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
15 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
16 Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.