Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH70UHD)

• DOT Name: Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1)
• Synonyms: Exchange factor smgGDS; SMG GDS protein; SMG P21 stimulatory GDP/GTP exchange protein
• Gene Name: RAP1GDS1
• Related Disease:
  T-cell acute lymphoblastic leukaemia
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Dementia
  Metastatic prostate carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Breast neoplasm
  Lymphoid leukemia
• UniProt ID: GDS1_HUMAN
• PDB ID: 5XGC; 5ZHX
• Pfam ID: PF00514
• Sequence:
  MDNLSDTLKKLKITAVDKTEDSLEGCLDCLLQALAQNNTETSEKIQASGILQLFASLLTP
  QSSCKAKVANIIAEVAKNEFMRIPCVDAGLISPLVQLLNSKDQEVLLQTGRALGNICYDS
  HEGRSAVDQAGGAQIVIDHLRSLCSITDPANEKLLTVFCGMLMNYSNENDSLQAQLINMG
  VIPTLVKLLGIHCQNAALTEMCLVAFGNLAELESSKEQFASTNIAEELVKLFKKQIEHDK
  REMIFEVLAPLAENDAIKLQLVEAGLVECLLEIVQQKVDSDKEDDITELKTGSDLMVLLL
  LGDESMQKLFEGGKGSVFQRVLSWIPSNNHQLQLAGALAIANFARNDANCIHMVDNGIVE
  KLMDLLDRHVEDGNVTVQHAALSALRNLAIPVINKAKMLSAGVTEAVLKFLKSEMPPVQF
  KLLGTLRMLIDAQAEAAEQLGKNVKLVERLVEWCEAKDHAGVMGESNRLLSALIRHSKSK
  DVIKTIVQSGGIKHLVTMATSEHVIMQNEALVALALIAALELGTAEKDLESAKLVQILHR
  LLADERSAPEIKYNSMVLICALMGSECLHKEVQDLAFLDVVSKLRSHENKSVAQQASLTE
  QRLTVES
• Function: Acts as a GEF (guanine nucleotide exchange factor) for the Rho family of small GTP-binding proteins (G proteins) that stimulates the dissociation of GDP to enable subsequent binding of GTP. Additionally, appears to chaperone the processing and/or trafficking of small GTPases containing a C-terminal polybasic region independently of GEF activity. Targets include RAP1A/RAP1B, RHOA, RHOB, RHOC, RAC1 and KRAS. Regulates mitochondrial dynamics by controlling RHOT function to promote mitochondrial fission during high calcium conditions. Able to promote the Ca(2+) release from the endoplasmic reticulum via both inositol trisphosphate (Ins3P) and ryanodine sensitive receptors leading to a enhanced mitochondrial Ca(2+) uptake ; [Isoform 1]: Acts as a GEF (guanine nucleotide exchange factor) for unprenylated RHOA. Chaperones the entry and passage of small GTPases through the prenylation pathway. Recognizes the last amino acid in the GTPase C-terminal CAAX motif with a preference for 'Leu' over 'Met', indicating involvement in the geranylgeranylation pathway ; [Isoform 2]: Acts as a GEF (guanine nucleotide exchange factor) for prenylated RHOA. Acts as a GEF for RHOC. Chaperones the downstream trafficking and/or processing of small newly prenylated GTPases. Escorts RAC1 to the nucleus.
• Reactome Pathway:
  RHOT1 GTPase cycle (R-HSA-9013425)
  RHOT2 GTPase cycle (R-HSA-9013419)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Dementia	DISXL1WY	Strong	Biomarker	[4]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[3]
Lymphoid leukemia	DIS65TYQ	Limited	Biomarker	[8]

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 Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[16]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rap1 GTPase-GDP dissociation stimulator 1 (RAP1GDS1).	[21]

References

• [1] NUP98/11p15 translocations affect CD34+ cells in myeloid and T lymphoid leukemias.Leuk Res. 2015 Jul;39(7):769-72. doi: 10.1016/j.leukres.2015.04.014. Epub 2015 May 7.
• [2] t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia.Br J Haematol. 2000 Jun;109(4):788-93. doi: 10.1046/j.1365-2141.2000.02106.x.
• [3] The SmgGDS splice variant SmgGDS-558 is a key promoter of tumor growth and RhoA signaling in breast cancer.Mol Cancer Res. 2014 Jan;12(1):130-42. doi: 10.1158/1541-7786.MCR-13-0362. Epub 2013 Nov 6.
• [4] Structural validity and internal consistency of the Qualidem in people with severe dementia.Int Psychogeriatr. 2017 Sep 4:1-11. doi: 10.1017/S1041610217001405. Online ahead of print.
• [5] SmgGDS is up-regulated in prostate carcinoma and promotes tumour phenotypes in prostate cancer cells.J Pathol. 2009 Feb;217(3):389-97. doi: 10.1002/path.2456.
• [6] SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers.Cell Cycle. 2014;13(6):941-52. doi: 10.4161/cc.27804. Epub 2014 Jan 16.
• [7] SmgGDS is a transient nucleolar protein that protects cells from nucleolar stress and promotes the cell cycle by regulating DREAM complex gene expression.Oncogene. 2017 Dec 14;36(50):6873-6883. doi: 10.1038/onc.2017.280. Epub 2017 Aug 14.
• [8] The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia.Blood. 1999 Sep 15;94(6):2072-9.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [15] 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.
• [16] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [17] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] 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.
• [20] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.