Details of Drug Off-Target (DOT)

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

DOT Name Ras-related protein Rap-1b (RAP1B)
Synonyms EC 3.6.5.2; GTP-binding protein smg p21B
Gene Name RAP1B
Related Disease
Adult glioblastoma ( )
Colorectal carcinoma ( )
Glioblastoma multiforme ( )
Thyroid cancer ( )
Thyroid gland carcinoma ( )
Thyroid tumor ( )
Adenoma ( )
Breast cancer ( )
Breast carcinoma ( )
Capillary malformation-arteriovenous malformation syndrome ( )
Cerebral cavernous malformation ( )
Cerebral cavernous malformation 3 ( )
Clear cell renal carcinoma ( )
Epithelial ovarian cancer ( )
Esophageal squamous cell carcinoma ( )
Gastric cancer ( )
Glioma ( )
Glomerulosclerosis ( )
Gonorrhea ( )
Kabuki syndrome ( )
Myelodysplastic syndrome ( )
Myotonic dystrophy ( )
Neoplasm ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Pancreatic cancer ( )
Pneumonia ( )
Pneumonitis ( )
Renal cell carcinoma ( )
Squamous cell carcinoma ( )
Stomach cancer ( )
Testicular germ cell tumor ( )
High blood pressure ( )
Neuroblastoma ( )
Thyroid gland follicular carcinoma ( )
Advanced cancer ( )
Hepatocellular carcinoma ( )
Parkinson disease ( )
Syndromic constitutional thrombocytopenia ( )
UniProt ID
RAP1B_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
3BRW; 3CF6; 4DXA; 4HDO; 4HDQ; 4M8N; 4MGI; 4MGK; 4MGY; 4MGZ; 4MH0; 5KHO; 6AXF; 6BA6; 6KYK; 6OQ3; 6OQ4; 6UZK; 7C7I; 7C7J; 8SU8; 8T7V
EC Number
3.6.5.2
Pfam ID
PF00071
Sequence
MREYKLVVLGSGGVGKSALTVQFVQGIFVEKYDPTIEDSYRKQVEVDAQQCMLEILDTAG
TEQFTAMRDLYMKNGQGFALVYSITAQSTFNDLQDLREQILRVKDTDDVPMILVGNKCDL
EDERVVGKEQGQNLARQWNNCAFLESSAKSKINVNEIFYDLVRQINRKTPVPGKARKKSS
CQLL
Function
GTP-binding protein that possesses intrinsic GTPase activity. Contributes to the polarizing activity of KRIT1 and CDH5 in the establishment and maintenance of correct endothelial cell polarity and vascular lumen. Required for the localization of phosphorylated PRKCZ, PARD3 and TIAM1 to the cell junction. Plays a role in the establishment of basal endothelial barrier function.
KEGG Pathway
MAPK sig.ling pathway (hsa04010 )
Ras sig.ling pathway (hsa04014 )
Rap1 sig.ling pathway (hsa04015 )
cAMP sig.ling pathway (hsa04024 )
Chemokine sig.ling pathway (hsa04062 )
Focal adhesion (hsa04510 )
Adherens junction (hsa04520 )
Platelet activation (hsa04611 )
Leukocyte transendothelial migration (hsa04670 )
Long-term potentiation (hsa04720 )
Neurotrophin sig.ling pathway (hsa04722 )
Cushing syndrome (hsa04934 )
Pancreatic secretion (hsa04972 )
Re.l cell carcinoma (hsa05211 )
Lipid and atherosclerosis (hsa05417 )
Reactome Pathway
GRB2 (R-HSA-354194 )
p130Cas linkage to MAPK signaling for integrins (R-HSA-372708 )
Rap1 signalling (R-HSA-392517 )
MAP2K and MAPK activation (R-HSA-5674135 )
Neutrophil degranulation (R-HSA-6798695 )
Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946 )
Signaling by high-kinase activity BRAF mutants (R-HSA-6802948 )
Signaling by BRAF and RAF1 fusions (R-HSA-6802952 )
Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955 )
MET activates RAP1 and RAC1 (R-HSA-8875555 )
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505 )
Signaling downstream of RAS mutants (R-HSA-9649948 )
Signaling by RAF1 mutants (R-HSA-9656223 )
Integrin signaling (R-HSA-354192 )

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Adult glioblastoma DISVP4LU Definitive Biomarker [1]
Colorectal carcinoma DIS5PYL0 Definitive Biomarker [2]
Glioblastoma multiforme DISK8246 Definitive Biomarker [1]
Thyroid cancer DIS3VLDH Definitive Altered Expression [3]
Thyroid gland carcinoma DISMNGZ0 Definitive Altered Expression [3]
Thyroid tumor DISLVKMD Definitive Altered Expression [3]
Adenoma DIS78ZEV Strong Biomarker [4]
Breast cancer DIS7DPX1 Strong Altered Expression [5]
Breast carcinoma DIS2UE88 Strong Altered Expression [5]
Capillary malformation-arteriovenous malformation syndrome DISMN03Q Strong Genetic Variation [6]
Cerebral cavernous malformation DISLKNYA Strong Biomarker [7]
Cerebral cavernous malformation 3 DISHAV0P Strong Biomarker [8]
Clear cell renal carcinoma DISBXRFJ Strong Biomarker [9]
Epithelial ovarian cancer DIS56MH2 Strong Altered Expression [10]
Esophageal squamous cell carcinoma DIS5N2GV Strong Biomarker [11]
Gastric cancer DISXGOUK Strong Altered Expression [12]
Glioma DIS5RPEH Strong Altered Expression [13]
Glomerulosclerosis DISJF20Z Strong Posttranslational Modification [14]
Gonorrhea DISQ5AO6 Strong Altered Expression [15]
Kabuki syndrome DISZN97H Strong Genetic Variation [16]
Myelodysplastic syndrome DISYHNUI Strong Genetic Variation [17]
Myotonic dystrophy DISNBEMX Strong Biomarker [18]
Neoplasm DISZKGEW Strong Altered Expression [19]
Ovarian cancer DISZJHAP Strong Altered Expression [10]
Ovarian neoplasm DISEAFTY Strong Altered Expression [10]
Pancreatic cancer DISJC981 Strong Altered Expression [20]
Pneumonia DIS8EF3M Strong Biomarker [21]
Pneumonitis DIS88E0K Strong Biomarker [21]
Renal cell carcinoma DISQZ2X8 Strong Biomarker [9]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [22]
Stomach cancer DISKIJSX Strong Altered Expression [12]
Testicular germ cell tumor DIS5RN24 Strong Biomarker [23]
High blood pressure DISY2OHH moderate Biomarker [24]
Neuroblastoma DISVZBI4 moderate Biomarker [25]
Thyroid gland follicular carcinoma DISFK2QT moderate Biomarker [26]
Advanced cancer DISAT1Z9 Limited Altered Expression [27]
Hepatocellular carcinoma DIS0J828 Limited Altered Expression [19]
Parkinson disease DISQVHKL Limited Biomarker [28]
Syndromic constitutional thrombocytopenia DISFXMTP Limited Autosomal dominant [29]
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⏷ Show the Full List of 39 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas 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 decreases the methylation of Ras-related protein Rap-1b (RAP1B). [30]
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12 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Ras-related protein Rap-1b (RAP1B). [31]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Ras-related protein Rap-1b (RAP1B). [32]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Ras-related protein Rap-1b (RAP1B). [33]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Ras-related protein Rap-1b (RAP1B). [34]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Ras-related protein Rap-1b (RAP1B). [35]
Zoledronate DMIXC7G Approved Zoledronate increases the expression of Ras-related protein Rap-1b (RAP1B). [36]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of Ras-related protein Rap-1b (RAP1B). [37]
Mifepristone DMGZQEF Approved Mifepristone increases the expression of Ras-related protein Rap-1b (RAP1B). [38]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Ras-related protein Rap-1b (RAP1B). [39]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Ras-related protein Rap-1b (RAP1B). [40]
Milchsaure DM462BT Investigative Milchsaure increases the expression of Ras-related protein Rap-1b (RAP1B). [41]
GALLICACID DM6Y3A0 Investigative GALLICACID decreases the expression of Ras-related protein Rap-1b (RAP1B). [42]
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⏷ Show the Full List of 12 Drug(s)

References

1 miR-128 and miR-149 enhance the chemosensitivity of temozolomide by Rap1B-mediated cytoskeletal remodeling in glioblastoma.Oncol Rep. 2014 Sep;32(3):957-64. doi: 10.3892/or.2014.3318. Epub 2014 Jul 10.
2 Regulation of RAP1B by miR-139 suppresses human colorectal carcinoma cell proliferation.Int J Biochem Cell Biol. 2012 Sep;44(9):1465-72. doi: 10.1016/j.biocel.2012.05.015. Epub 2012 May 27.
3 miR-206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B.J Cell Biochem. 2019 Nov;120(11):18927-18936. doi: 10.1002/jcb.29213. Epub 2019 Jun 27.
4 Molecular mechanisms underlying the tumorigenesis of colorectal adenomas: correlation to activated K-ras oncogene.Oncol Rep. 2006 Dec;16(6):1245-52.
5 Phospholipase Cgamma1 is required for metastasis development and progression.Cancer Res. 2008 Dec 15;68(24):10187-96. doi: 10.1158/0008-5472.CAN-08-1181.
6 RASA1 regulates the function of lymphatic vessel valves in mice.J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.
7 Combinatorial interaction between CCM pathway genes precipitates hemorrhagic stroke.Dis Model Mech. 2008 Nov-Dec;1(4-5):275-81. doi: 10.1242/dmm.000513. Epub 2008 Oct 28.
8 Sporadic cerebral cavernous malformations: report of further mutations of CCM genes in 40 Italian patients.Biomed Res Int. 2013;2013:459253. doi: 10.1155/2013/459253. Epub 2013 Aug 22.
9 miR-28-5p acts as a tumor suppressor in renal cell carcinoma for multiple antitumor effects by targeting RAP1B.Oncotarget. 2016 Nov 8;7(45):73888-73902. doi: 10.18632/oncotarget.12516.
10 Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B.Nat Commun. 2015 Jan 8;6:5917. doi: 10.1038/ncomms6917.
11 RAP1B, a DVL2 binding protein, activates Wnt/beta-catenin signaling in esophageal squamous cell carcinoma.Gene. 2017 May 5;611:15-20. doi: 10.1016/j.gene.2017.01.021. Epub 2017 Jan 21.
12 Knockdown of Rap1b Enhances Apoptosis and Autophagy in Gastric Cancer Cells via the PI3K/Akt/mTOR Pathway.Oncol Res. 2016;24(5):287-293. doi: 10.3727/096504016X14648701447779.
13 Long non-coding RNA MALAT1 promotes proliferation and suppresses apoptosis of glioma cells through derepressing Rap1B by sponging miR-101.J Neurooncol. 2017 Aug;134(1):19-28. doi: 10.1007/s11060-017-2498-5. Epub 2017 May 27.
14 Podocyte-specific RAP1GAP expression contributes to focal segmental glomerulosclerosis-associated glomerular injury.J Clin Invest. 2014 Apr;124(4):1757-69. doi: 10.1172/JCI67846. Epub 2014 Mar 18.
15 Expression of RAP1B is associated with poor prognosis and promotes an aggressive phenotype in gastric cancer.Oncol Rep. 2015 Nov;34(5):2385-94. doi: 10.3892/or.2015.4234. Epub 2015 Sep 1.
16 RAP1-mediated MEK/ERK pathway defects in Kabuki syndrome.J Clin Invest. 2015 Sep;125(9):3585-99. doi: 10.1172/JCI80102. Epub 2015 Aug 17.
17 Mutation in RAP1 is a rare event in myelodysplastic syndromes.Leukemia. 2005 Sep;19(9):1678-80. doi: 10.1038/sj.leu.2403882.
18 The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.EMBO J. 1996 Apr 15;15(8):1885-93.
19 Rap1b enhances the invasion and migration of hepatocellular carcinoma cells by up-regulating Twist 1.Exp Cell Res. 2018 Jun 1;367(1):56-64. doi: 10.1016/j.yexcr.2018.03.019. Epub 2018 Mar 17.
20 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.
21 The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation.J Exp Med. 2014 Aug 25;211(9):1741-58. doi: 10.1084/jem.20131706. Epub 2014 Aug 4.
22 Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma.Am J Pathol. 2006 Feb;168(2):585-96. doi: 10.2353/ajpath.2006.050132.
23 Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour.BJU Int. 2001 Feb;87(3):227-31. doi: 10.1046/j.1464-410x.2001.02030.x.
24 Rap1b in smooth muscle and endothelium is required for maintenance of vascular tone and normal blood pressure.Arterioscler Thromb Vasc Biol. 2014 Jul;34(7):1486-94. doi: 10.1161/ATVBAHA.114.303678. Epub 2014 May 1.
25 HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway.J Neurochem. 2004 Nov;91(3):613-22. doi: 10.1111/j.1471-4159.2004.02754.x.
26 Deletion of Rap1b, but not Rap1a or Epac1, Reduces Protein Kinase A-Mediated Thyroid Cancer.Thyroid. 2018 Sep;28(9):1153-1161. doi: 10.1089/thy.2017.0528. Epub 2018 Aug 2.
27 Function, Significance, and Regulation of Rap1b in Malignancy.Crit Rev Eukaryot Gene Expr. 2019;29(2):151-160. doi: 10.1615/CritRevEukaryotGeneExpr.2019025997.
28 GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.Biochemistry. 2007 Feb 6;46(5):1380-8. doi: 10.1021/bi061960m.
29 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
30 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.
31 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.
32 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
33 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
34 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
35 Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
36 Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
37 Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
38 Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
39 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.
40 Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
41 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
42 Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.