Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWC3Z3R)

DOT Name Rab5 GDP/GTP exchange factor (RABGEF1)
Synonyms RAP1; Rabaptin-5-associated exchange factor for Rab5; Rabex-5
Gene Name RABGEF1
Related Disease
Crohn disease ( )
Inflammatory bowel disease ( )
Prostate cancer ( )
Prostate carcinoma ( )
Ulcerative colitis ( )
Acute myelogenous leukaemia ( )
Adult glioblastoma ( )
Advanced cancer ( )
Alzheimer disease ( )
Bone osteosarcoma ( )
Breast cancer ( )
Breast carcinoma ( )
Cerebral cavernous malformation ( )
Colon cancer ( )
Colon carcinoma ( )
Colorectal carcinoma ( )
Depression ( )
Dermatitis ( )
Diabetic kidney disease ( )
Gastric cancer ( )
Glioblastoma multiforme ( )
Hepatocellular carcinoma ( )
Lung adenocarcinoma ( )
Metastatic malignant neoplasm ( )
Myocardial infarction ( )
Neuroblastoma ( )
Obesity ( )
Osteosarcoma ( )
Ovarian cancer ( )
Pancreatic cancer ( )
Plasma cell myeloma ( )
Schizophrenia ( )
Squamous cell carcinoma ( )
Stomach cancer ( )
Tuberous sclerosis ( )
Head-neck squamous cell carcinoma ( )
High blood pressure ( )
Renal fibrosis ( )
Carcinoma of liver and intrahepatic biliary tract ( )
Colitis ( )
Fatty liver disease ( )
Liver cancer ( )
Melanoma ( )
Non-small-cell lung cancer ( )
Rheumatoid arthritis ( )
Small lymphocytic lymphoma ( )
Stroke ( )
UniProt ID
RABX5_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1TXU; 2C7M; 2C7N; 2OT3; 4N3X; 4N3Y; 4N3Z; 4Q9U
Pfam ID
PF18151 ; PF02204 ; PF01754
Sequence
MSLKSERRGIHVDQSDLLCKKGCGYYGNPAWQGFCSKCWREEYHKARQKQIQEDWELAER
LQREEEEAFASSQSSQGAQSLTFSKFEEKKTNEKTRKVTTVKKFFSASSRVGSKKEIQEA
KAPSPSINRQTSIETDRVSKEFIEFLKTFHKTGQEIYKQTKLFLEGMHYKRDLSIEEQSE
CAQDFYHNVAERMQTRGKVPPERVEKIMDQIEKYIMTRLYKYVFCPETTDDEKKDLAIQK
RIRALRWVTPQMLCVPVNEDIPEVSDMVVKAITDIIEMDSKRVPRDKLACITKCSKHIFN
AIKITKNEPASADDFLPTLIYIVLKGNPPRLQSNIQYITRFCNPSRLMTGEDGYYFTNLC
CAVAFIEKLDAQSLNLSQEDFDRYMSGQTSPRKQEAESWSPDACLGVKQMYKNLDLLSQL
NERQERIMNEAKKLEKDLIDWTDGIAREVQDIVEKYPLEIKPPNQPLAAIDSENVENDKL
PPPLQPQVYAG
Function
Rab effector protein acting as linker between gamma-adaptin, RAB4A or RAB5A. Involved in endocytic membrane fusion and membrane trafficking of recycling endosomes. Stimulates nucleotide exchange on RAB5A. Can act as a ubiquitin ligase.
KEGG Pathway
Mitophagy - animal (hsa04137 )
Reactome Pathway
RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198 )
TBC/RABGAPs (R-HSA-8854214 )

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Crohn disease DIS2C5Q8 Definitive Biomarker [1]
Inflammatory bowel disease DISGN23E Definitive Altered Expression [1]
Prostate cancer DISF190Y Definitive Altered Expression [2]
Prostate carcinoma DISMJPLE Definitive Altered Expression [2]
Ulcerative colitis DIS8K27O Definitive Biomarker [1]
Acute myelogenous leukaemia DISCSPTN Strong Genetic Variation [3]
Adult glioblastoma DISVP4LU Strong Biomarker [4]
Advanced cancer DISAT1Z9 Strong Altered Expression [5]
Alzheimer disease DISF8S70 Strong Biomarker [6]
Bone osteosarcoma DIST1004 Strong Biomarker [7]
Breast cancer DIS7DPX1 Strong Biomarker [8]
Breast carcinoma DIS2UE88 Strong Biomarker [8]
Cerebral cavernous malformation DISLKNYA Strong Biomarker [9]
Colon cancer DISVC52G Strong Altered Expression [10]
Colon carcinoma DISJYKUO Strong Altered Expression [10]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [11]
Depression DIS3XJ69 Strong Altered Expression [12]
Dermatitis DISY5SZC Strong Genetic Variation [13]
Diabetic kidney disease DISJMWEY Strong Biomarker [14]
Gastric cancer DISXGOUK Strong Altered Expression [15]
Glioblastoma multiforme DISK8246 Strong Biomarker [4]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [16]
Lung adenocarcinoma DISD51WR Strong Biomarker [17]
Metastatic malignant neoplasm DIS86UK6 Strong Altered Expression [18]
Myocardial infarction DIS655KI Strong Biomarker [19]
Neuroblastoma DISVZBI4 Strong Altered Expression [20]
Obesity DIS47Y1K Strong Biomarker [16]
Osteosarcoma DISLQ7E2 Strong Biomarker [7]
Ovarian cancer DISZJHAP Strong Biomarker [21]
Pancreatic cancer DISJC981 Strong Altered Expression [22]
Plasma cell myeloma DIS0DFZ0 Strong Biomarker [23]
Schizophrenia DISSRV2N Strong Genetic Variation [24]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [25]
Stomach cancer DISKIJSX Strong Altered Expression [15]
Tuberous sclerosis DISEMUGZ Strong Altered Expression [26]
Head-neck squamous cell carcinoma DISF7P24 moderate Biomarker [27]
High blood pressure DISY2OHH moderate Biomarker [28]
Renal fibrosis DISMHI3I moderate Biomarker [14]
Carcinoma of liver and intrahepatic biliary tract DIS8WA0W Limited Biomarker [16]
Colitis DISAF7DD Limited Genetic Variation [29]
Fatty liver disease DIS485QZ Limited Biomarker [16]
Liver cancer DISDE4BI Limited Biomarker [16]
Melanoma DIS1RRCY Limited Altered Expression [30]
Non-small-cell lung cancer DIS5Y6R9 Limited Biomarker [31]
Rheumatoid arthritis DISTSB4J Limited Altered Expression [32]
Small lymphocytic lymphoma DIS30POX Limited Biomarker [33]
Stroke DISX6UHX Limited Altered Expression [34]
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⏷ Show the Full List of 47 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate affects the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [35]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [36]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [37]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [38]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [39]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [40]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [42]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Rab5 GDP/GTP exchange factor (RABGEF1). [43]
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⏷ Show the Full List of 8 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Rab5 GDP/GTP exchange factor (RABGEF1). [41]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of Rab5 GDP/GTP exchange factor (RABGEF1). [41]
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References

1 Altered mRNA expression of telomere binding proteins (TPP1, POT1, RAP1, TRF1 and TRF2) in ulcerative colitis and Crohn's disease.Dig Liver Dis. 2010 Aug;42(8):544-8. doi: 10.1016/j.dld.2009.12.005. Epub 2010 Jan 12.
2 Expression of RABEX-5 and its clinical significance in prostate cancer.J Exp Clin Cancer Res. 2014 Apr 9;33(1):31. doi: 10.1186/1756-9966-33-31.
3 Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
4 The Ras-related protein, Rap1A, mediates thrombin-stimulated, integrin-dependent glioblastoma cell proliferation and tumor growth.J Biol Chem. 2014 Jun 20;289(25):17689-98. doi: 10.1074/jbc.M113.536227. Epub 2014 May 1.
5 Ras and Rap1: A tale of two GTPases.Semin Cancer Biol. 2019 Feb;54:29-39. doi: 10.1016/j.semcancer.2018.03.005. Epub 2018 Apr 3.
6 Modifying Rap1-signalling by targeting Pde6 is neuroprotective in models of Alzheimer's disease.Mol Neurodegener. 2018 Sep 26;13(1):50. doi: 10.1186/s13024-018-0283-3.
7 Telomere stability genes are not mutated in osteosarcoma cell lines.Cancer Genet Cytogenet. 2005 Jul 1;160(1):79-81. doi: 10.1016/j.cancergencyto.2004.12.004.
8 The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals.Int J Mol Sci. 2019 May 30;20(11):2653. doi: 10.3390/ijms20112653.
9 miR-21 coordinates tumor growth and modulates KRIT1 levels.Biochem Biophys Res Commun. 2013 Aug 16;438(1):90-6. doi: 10.1016/j.bbrc.2013.07.031. Epub 2013 Jul 18.
10 Rap1 regulates hematopoietic stem cell survival and affects oncogenesis and response to chemotherapy.Nat Commun. 2019 Dec 13;10(1):5349. doi: 10.1038/s41467-019-13082-9.
11 Higher RABEX-5 mRNA predicts unfavourable survival in patients with colorectal cancer.Eur Rev Med Pharmacol Sci. 2017 May;21(10):2372-2376.
12 Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims.Arch Gen Psychiatry. 2006 Jun;63(6):639-48. doi: 10.1001/archpsyc.63.6.639.
13 Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis.J Clin Invest. 2016 Dec 1;126(12):4497-4515. doi: 10.1172/JCI86359. Epub 2016 Nov 7.
14 A Glimpse of the Mechanisms Related to Renal Fibrosis in Diabetic Nephropathy.Adv Exp Med Biol. 2019;1165:49-79. doi: 10.1007/978-981-13-8871-2_4.
15 RABEX-5 is upregulated and plays an oncogenic role in gastric cancer development by activating the VEGF signaling pathway.PLoS One. 2014 Nov 26;9(11):e113891. doi: 10.1371/journal.pone.0113891. eCollection 2014.
16 Mice lacking RAP1 show early onset and higher rates of DEN-induced hepatocellular carcinomas in female mice.PLoS One. 2018 Oct 11;13(10):e0204909. doi: 10.1371/journal.pone.0204909. eCollection 2018.
17 CRKL as a lung cancer oncogene and mediator of acquired resistance to EGFR inhibitors: is it all that it is cracked up to be?.Cancer Discov. 2011 Dec;1(7):560-1. doi: 10.1158/2159-8290.CD-11-0295.
18 RABEX-5 plays an oncogenic role in breast cancer by activating MMP-9 pathway.J Exp Clin Cancer Res. 2013 Aug 13;32(1):52. doi: 10.1186/1756-9966-32-52.
19 Epac-Rap1-activated mesenchymal stem cells improve cardiac function in rat model of myocardial infarction.Cardiovasc Ther. 2017 Apr;35(2). doi: 10.1111/1755-5922.12248.
20 MicroRNA-149 is associated with clinical outcome in human neuroblastoma and modulates cancer cell proliferation through Rap1 independent of MYCN amplification.Biochimie. 2017 Aug;139:1-8. doi: 10.1016/j.biochi.2017.04.011. Epub 2017 Apr 27.
21 DOCK4, a GTPase activator, is disrupted during tumorigenesis.Cell. 2003 Mar 7;112(5):673-84. doi: 10.1016/s0092-8674(03)00155-7.
22 An adenosine-mediated signaling pathway suppresses prenylation of the GTPase Rap1B and promotes cell scattering.Sci Signal. 2013 May 28;6(277):ra39. doi: 10.1126/scisignal.2003374.
23 Expression profile of shelterin components in plasma cell disorders. Clinical significance of POT1 overexpression.Blood Cells Mol Dis. 2014 Feb-Mar;52(2-3):134-9. doi: 10.1016/j.bcmd.2013.10.002. Epub 2013 Nov 14.
24 PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors.Cell Rep. 2018 Jan 9;22(2):456-470. doi: 10.1016/j.celrep.2017.12.044.
25 RAP1 GTPase overexpression is associated with cervical intraepithelial neoplasia.PLoS One. 2015 Apr 9;10(4):e0123531. doi: 10.1371/journal.pone.0123531. eCollection 2015.
26 Rap1 activity is elevated in malignant astrocytomas independent of tuberous sclerosis complex-2 gene expression.Int J Oncol. 2003 Jan;22(1):195-200.
27 Inactivation or loss of TTP promotes invasion in head and neck cancer via transcript stabilization and secretion of MMP9, MMP2, and IL-6.Clin Cancer Res. 2013 Mar 1;19(5):1169-79. doi: 10.1158/1078-0432.CCR-12-2927. Epub 2013 Jan 24.
28 Rap1 promotes endothelial mechanosensing complex formation, NO release and normal endothelial function.EMBO Rep. 2015 May;16(5):628-37. doi: 10.15252/embr.201439846. Epub 2015 Mar 25.
29 Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling.Mucosal Immunol. 2020 Jan;13(1):96-109. doi: 10.1038/s41385-019-0211-z. Epub 2019 Oct 18.
30 SHARPIN Promotes Melanoma Progression viaRap1 Signaling Pathway.J Invest Dermatol. 2020 Feb;140(2):395-403.e6. doi: 10.1016/j.jid.2019.07.696. Epub 2019 Aug 8.
31 Combination of Gentiana rhodantha and Gerbera anandria in the BL02 formula as therapeutics to non-small cell lung carcinoma acting via Rap1/cdc42 signaling: A transcriptomics/ bio-informatics biological validation approach.Pharmacol Res. 2020 May;155:104415. doi: 10.1016/j.phrs.2019.104415. Epub 2019 Aug 26.
32 CTLA-4IG suppresses reactive oxygen species by preventing synovial adherent cell-induced inactivation of Rap1, a Ras family GTPASE mediator of oxidative stress in rheumatoid arthritis T cells.Arthritis Rheum. 2006 Oct;54(10):3135-43. doi: 10.1002/art.22139.
33 Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells.Blood Adv. 2018 Jul 10;2(13):1551-1561. doi: 10.1182/bloodadvances.2017014506.
34 Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation.Circulation. 2019 Jul 23;140(4):319-335. doi: 10.1161/CIRCULATIONAHA.118.039345. Epub 2019 Jun 3.
35 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
36 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.
37 Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
38 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
39 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
40 New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
41 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.
42 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
43 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.