Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKRO61U)

• DOT Name: Ras-related C3 botulinum toxin substrate 1 (RAC1)
• Synonyms: EC 3.6.5.2; Cell migration-inducing gene 5 protein; Ras-like protein TC25; p21-Rac1
• Gene Name: RAC1
• Related Disease: Intellectual disability, autosomal dominant 48
• UniProt ID: RAC1_HUMAN
• PDB ID: 1E96 ; 1FOE ; 1G4U ; 1HE1 ; 1HH4 ; 1I4D ; 1I4L ; 1I4T ; 1MH1 ; 1RYF ; 1RYH ; 2FJU ; 2H7V ; 2NZ8 ; 2P2L ; 2RMK ; 2VRW ; 2WKP ; 2WKQ ; 2WKR ; 2YIN ; 3B13 ; 3BJI ; 3RYT ; 3SBD ; 3SBE ; 3SU8 ; 3SUA ; 3TH5 ; 4GZL ; 4GZM ; 4YON ; 5FI0 ; 5HZH ; 5N6O ; 5O33 ; 5QQD ; 5QQE ; 5QQF ; 5QQG ; 5QQH ; 5QQI ; 5QQJ ; 5QQK ; 5QQL ; 5QQM ; 5QQN ; 5QU9 ; 6AGP ; 6BC1 ; 6TGC ; 6X1G ; 7AJK ; 7DPA ; 7SJ4 ; 7USD ; 7USE ; 8I5V ; 8I5W
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MQAIKCVVVGDGAVGKTCLLISYTTNAFPGEYIPTVFDNYSANVMVDGKPVNLGLWDTAG
  QEDYDRLRPLSYPQTDVFLICFSLVSPASFENVRAKWYPEVRHHCPNTPIILVGTKLDLR
  DDKDTIEKLKEKKLTPITYPQGLAMAKEIGAVKYLECSALTQRGLKTVFDEAIRAVLCPP
  PVKKRKRKCLLL
• Function: Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity. In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization; [Isoform B]: Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.
• Tissue Specificity: Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.
• 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)
  Sphingolipid sig.ling pathway (hsa04071)
  Phagosome (hsa04145)
  Efferocytosis (hsa04148)
  PI3K-Akt sig.ling pathway (hsa04151)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor sig.ling pathway (hsa04620)
  .tural killer cell mediated cytotoxicity (hsa04650)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leukocyte transendothelial migration (hsa04670)
  Neurotrophin sig.ling pathway (hsa04722)
  Regulation of actin cytoskeleton (hsa04810)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Pancreatic secretion (hsa04972)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Bacterial invasion of epithelial cells (hsa05100)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Re.l cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Choline metabolism in cancer (hsa05231)
  Diabetic cardiomyopathy (hsa05415)
  Viral myocarditis (hsa05416)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by SCF-KIT (R-HSA-1433557)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)
  Nef and signal transduction (R-HSA-164944)
  NRAGE signals death through JNK (R-HSA-193648)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  DAP12 signaling (R-HSA-2424491)
  FCERI mediated MAPK activation (R-HSA-2871796)
  DSCAM interactions (R-HSA-376172)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  EPHB-mediated forward signaling (R-HSA-3928662)
  Ephrin signaling (R-HSA-3928664)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Sema3A PAK dependent Axon repulsion (R-HSA-399954)
  SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion (R-HSA-399955)
  PCP/CE pathway (R-HSA-4086400)
  Sema4D mediated inhibition of cell attachment and migration (R-HSA-416550)
  DCC mediated attractive signaling (R-HSA-418885)
  Activation of RAC1 (R-HSA-428540)
  Inactivation of CDC42 and RAC1 (R-HSA-428543)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Signal transduction by L1 (R-HSA-445144)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  RHO GTPases activate PKNs (R-HSA-5625740)
  RHO GTPases activate CIT (R-HSA-5625900)
  RHO GTPases activate KTN1 (R-HSA-5625970)
  RHO GTPases activate IQGAPs (R-HSA-5626467)
  RHO GTPases activate PAKs (R-HSA-5627123)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RHO GTPases Activate Formins (R-HSA-5663220)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Neutrophil degranulation (R-HSA-6798695)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471)
  MET activates RAP1 and RAC1 (R-HSA-8875555)
  RAC1 GTPase cycle (R-HSA-9013149)
  NTRK2 activates RAC1 (R-HSA-9032759)
  Activated NTRK2 signals through CDK5 (R-HSA-9032845)
  Activation of RAC1 downstream of NMDARs (R-HSA-9619229)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  WNT5 (R-HSA-9673324)
  Azathioprine ADME (R-HSA-9748787)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability, autosomal dominant 48	DISF38NT	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
PD-0325901	DM27D4J	Phase 2	Ras-related C3 botulinum toxin substrate 1 (RAC1) affects the response to substance of PD-0325901.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[7]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[9]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the activity of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[10]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[12]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[13]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the activity of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[14]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[15]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the activity of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[14]
Mebendazole	DMO14SG	Approved	Mebendazole decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[16]
Plitidepsin	DMJ8AUE	Phase 3	Plitidepsin increases the activity of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[19]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[27]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[29]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[29]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Ethanol increases the localization of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol affects the localization of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[17]
D-glucose	DMMG2TO	Investigative	D-glucose increases the localization of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[28]
Piceatannol	DMYOP45	Investigative	Piceatannol affects the localization of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[17]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[21]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ras-related C3 botulinum toxin substrate 1 (RAC1).	[22]

References

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• [5] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [6] 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.
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• [8] Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. Toxicology. 2009 Feb 27;256(3):183-90. doi: 10.1016/j.tox.2008.11.016. Epub 2008 Nov 28.
• [9] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
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• [14] Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras. Oncol Rep. 2009 May;21(5):1317-22. doi: 10.3892/or_00000357.
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• [18] Plitidepsin has a dual effect inhibiting cell cycle and inducing apoptosis via Rac1/c-Jun NH2-terminal kinase activation in human melanoma cells. J Pharmacol Exp Ther. 2008 Mar;324(3):1093-101. doi: 10.1124/jpet.107.132662. Epub 2007 Dec 18.
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• [22] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
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