Details of Drug Off-Target (DOT)

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

• DOT Name: SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2)
• Synonyms: srGAP2; Formin-binding protein 2; Rho GTPase-activating protein 34
• Gene Name: SRGAP2
• Related Disease:
  Narcolepsy
  Oral lichen planus
  Breast cancer
  Breast carcinoma
  Chondrosarcoma
  Diabetic kidney disease
  Infantile epileptic-dyskinetic encephalopathy
  Melanoma
  Neoplasm
  Retinoblastoma
  Bone osteosarcoma
  Metastatic malignant neoplasm
  Osteosarcoma
  Advanced cancer
  Intellectual disability
• UniProt ID: SRGP2_HUMAN
• PDB ID: 2DL8; 4RTT; 4RUG; 5I6J; 5I6R; 5I7D
• Pfam ID: PF00611 ; PF00620 ; PF00018
• Sequence:
  MTSPAKFKKDKEIIAEYDTQVKEIRAQLTEQMKCLDQQCELRVQLLQDLQDFFRKKAEIE
  MDYSRNLEKLAERFLAKTRSTKDQQFKKDQNVLSPVNCWNLLLNQVKRESRDHTTLSDIY
  LNNIIPRFVQVSEDSGRLFKKSKEVGQQLQDDLMKVLNELYSVMKTYHMYNADSISAQSK
  LKEAEKQEEKQIGKSVKQEDRQTPRSPDSTANVRIEEKHVRRSSVKKIEKMKEKRQAKYT
  ENKLKAIKARNEYLLALEATNASVFKYYIHDLSDLIDQCCDLGYHASLNRALRTFLSAEL
  NLEQSKHEGLDAIENAVENLDATSDKQRLMEMYNNVFCPPMKFEFQPHMGDMASQLCAQQ
  PVQSELVQRCQQLQSRLSTLKIENEEVKKTMEATLQTIQDIVTVEDFDVSDCFQYSNSME
  SVKSTVSETFMSKPSIAKRRANQQETEQFYFTKMKEYLEGRNLITKLQAKHDLLQKTLGE
  SQRTDCSLARRSSTVRKQDSSQAIPLVVESCIRFISRHGLQHEGIFRVSGSQVEVNDIKN
  AFERGEDPLAGDQNDHDMDSIAGVLKLYFRGLEHPLFPKDIFHDLMACVTMDNLQERALH
  IRKVLLVLPKTTLIIMRYLFAFLNHLSQFSEENMMDPYNLAICFGPSLMSVPEGHDQVSC
  QAHVNELIKTIIIQHENIFPSPRELEGPVYSRGGSMEDYCDSPHGETTSVEDSTQDVTAE
  HHTSDDECEPIEAIAKFDYVGRTARELSFKKGASLLLYQRASDDWWEGRHNGIDGLIPHQ
  YIVVQDTEDGVVERSSPKSEIEVISEPPEEKVTARAGASCPSGGHVADIYLANINKQRKR
  PESGSIRKTFRSDSHGLSSSLTDSSSPGVGASCRPSSQPIMSQSLPKEGPDKCSISGHGS
  LNSISRHSSLKNRLDSPQIRKTATAGRSKSFNNHRPMDPEVIAQDIEATMNSALNELREL
  ERQSSVKHTPDVVLDTLEPLKTSPVVAPTSEPSSPLHTQLLKDPEPAFQRSASTAGDIAC
  AFRPVKSVKMAAPVKPPATRPKPTVFPKTNATSPGVNSSTSPQSTDKSCTV
• Function: Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex. Regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons. SRGAP2/SRGAP2A limits excitatory and inhibitory synapse density through its RAC1-specific GTPase activating activity, while it promotes maturation of both excitatory and inhibitory synapses through its ability to bind to the postsynaptic scaffolding protein HOMER1 at excitatory synapses, and the postsynaptic protein GPHN at inhibitory synapses. Mechanistically, acts by binding and deforming membranes, thereby regulating actin dynamics to regulate cell migration and differentiation. Promotes cell repulsion and contact inhibition of locomotion: localizes to protrusions with curved edges and controls the duration of RAC1 activity in contact protrusions. In non-neuronal cells, may also play a role in cell migration by regulating the formation of lamellipodia and filopodia.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  RHO GTPases Activate Formins (R-HSA-5663220)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOU GTPase cycle (R-HSA-9013420)
  RAC3 GTPase cycle (R-HSA-9013423)
  RHOF GTPase cycle (R-HSA-9035034)
  Inactivation of CDC42 and RAC1 (R-HSA-428543)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Oral lichen planus	DISVEAJA	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Chondrosarcoma	DIS4I7JB	Strong	Altered Expression	[4]
Diabetic kidney disease	DISJMWEY	Strong	Altered Expression	[5]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[6]
Melanoma	DIS1RRCY	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[4]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[7]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[7]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Intellectual disability	DISMBNXP	Limited	Biomarker	[9]

17 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 SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[18]
Menadione	DMSJDTY	Approved	Menadione affects the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[16]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[25]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid decreases the expression of SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[26]

1 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 SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2).	[22]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] A combinative analysis of gene expression profiles and microRNA expression profiles identifies critical genes and microRNAs in oral lichen planus.Arch Oral Biol. 2016 Aug;68:61-5. doi: 10.1016/j.archoralbio.2016.03.018. Epub 2016 Mar 30.
• [3] Genetic variants at 1p11.2 and breast cancer risk: a two-stage study in Chinese women.PLoS One. 2011;6(6):e21563. doi: 10.1371/journal.pone.0021563. Epub 2011 Jun 27.
• [4] FNBP2 gene on human chromosome 1q32.1 encodes ARHGAP family protein with FCH, FBH, RhoGAP and SH3 domains.Int J Mol Med. 2003 Jun;11(6):791-7.
• [5] Dissection of Glomerular Transcriptional Profile in Patients With Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function.Diabetes. 2018 Apr;67(4):717-730. doi: 10.2337/db17-0755. Epub 2017 Dec 14.
• [6] Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2).Am J Med Genet A. 2012 Jan;158A(1):199-205. doi: 10.1002/ajmg.a.34363. Epub 2011 Nov 21.
• [7] Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma.Sci Rep. 2016 Dec 14;6:39059. doi: 10.1038/srep39059.
• [8] Molecular characteristics of recurrent triple-negative breast cancer.Mol Med Rep. 2015 Nov;12(5):7326-34. doi: 10.3892/mmr.2015.4360. Epub 2015 Sep 24.
• [9] The inverse F-BAR domain protein srGAP2 acts through srGAP3 to modulate neuronal differentiation and neurite outgrowth of mouse neuroblastoma cells.PLoS One. 2013;8(3):e57865. doi: 10.1371/journal.pone.0057865. Epub 2013 Mar 7.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [15] 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.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [22] 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.
• [23] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [24] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.