Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUX685J)

• DOT Name: Sprouty-related, EVH1 domain-containing protein 2 (SPRED2)
• Synonyms: Spred-2
• Gene Name: SPRED2
• Related Disease:
  Achondroplasia
  Alzheimer disease
  Cardiovascular disease
  Hepatocellular carcinoma
  Metastatic malignant neoplasm
  Multiple sclerosis
  Noonan syndrome 14
  Obsessive compulsive disorder
  Rheumatoid arthritis
  Schizophrenia
  Autoimmune disease
  Immune system disorder
  Neoplasm
  Arrhythmia
  Obesity
  Prostate cancer
  Prostate carcinoma
  Systemic lupus erythematosus
• UniProt ID: SPRE2_HUMAN
• PDB ID: 2JP2; 8EQ5
• Pfam ID: PF05210 ; PF00568
• Sequence:
  MTEETHPDDDSYIVRVKAVVMTRDDSSGGWFPQEGGGISRVGVCKVMHPEGNGRSGFLIH
  GERQKDKLVVLECYVRKDLVYTKANPTFHHWKVDNRKFGLTFQSPADARAFDRGVRKAIE
  DLIEGSTTSSSTIHNEAELGDDDVFTTATDSSSNSSQKREQPTRTISSPTSCEHRRIYTL
  GHLHDSYPTDHYHLDQPMPRPYRQVSFPDDDEEIVRINPREKIWMTGYEDYRHAPVRGKY
  PDPSEDADSSYVRFAKGEVPKHDYNYPYVDSSDFGLGEDPKGRGGSVIKTQPSRGKSRRR
  KEDGERSRCVYCRDMFNHEENRRGHCQDAPDSVRTCIRRVSCMWCADSMLYHCMSDPEGD
  YTDPCSCDTSDEKFCLRWMALIALSFLAPCMCCYLPLRACYHCGVMCRCCGGKHKAAA
• Function: Negatively regulates Ras signaling pathways and downstream activation of MAP kinases. Recruits and translocates NF1 to the cell membrane, thereby enabling NF1-dependent hydrolysis of active GTP-bound Ras to inactive GDP-bound Ras. Inhibits fibroblast growth factor (FGF)-induced retinal lens fiber differentiation, probably by inhibiting FGF-mediated phosphorylation of ERK1/2. Inhibits TGFB-induced epithelial-to-mesenchymal transition in lens epithelial cells.
• Tissue Specificity: Expressed in liver, skin, small intestine, salivary gland and prostate.
• Reactome Pathway:
  FGFRL1 modulation of FGFR1 signaling (R-HSA-5658623)
  RAS signaling downstream of NF1 loss-of-function variants (R-HSA-6802953)
  Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Achondroplasia	DISYWN2O	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Noonan syndrome 14	DISZTKRJ	Strong	Autosomal recessive	[7]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[10]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[11]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[11]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[12]
Arrhythmia	DISFF2NI	Limited	Biomarker	[13]
Obesity	DIS47Y1K	Limited	Biomarker	[14]
Prostate cancer	DISF190Y	Limited	Altered Expression	[12]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[12]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[15]

3 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 Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[28]

16 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 Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[32]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Sprouty-related, EVH1 domain-containing protein 2 (SPRED2).	[33]

References

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• [2] Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
• [3] Oxidized low-density lipoprotein is a common risk factor for cardiovascular diseases and gastroenterological cancers via epigenomical regulation of microRNA-210.Oncotarget. 2015 Sep 15;6(27):24105-18. doi: 10.18632/oncotarget.4152.
• [4] Regulation of human hepatocellular carcinoma cells by Spred2 and correlative studies on its mechanism.Biochem Biophys Res Commun. 2011 Jul 15;410(4):803-8. doi: 10.1016/j.bbrc.2011.06.068. Epub 2011 Jun 15.
• [5] Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway.J Exp Clin Cancer Res. 2019 Sep 6;38(1):393. doi: 10.1186/s13046-019-1408-4.
• [6] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [7] SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype. Am J Hum Genet. 2021 Nov 4;108(11):2112-2129. doi: 10.1016/j.ajhg.2021.09.007. Epub 2021 Oct 8.
• [8] OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.Mol Psychiatry. 2018 Feb;23(2):444-458. doi: 10.1038/mp.2016.232. Epub 2017 Jan 10.
• [9] Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.Hum Mol Genet. 2019 Mar 1;28(5):858-874. doi: 10.1093/hmg/ddy395.
• [10] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [11] Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
• [12] Evidence for downregulation of the negative regulator SPRED2 in clinical prostate cancer.Br J Cancer. 2013 Feb 19;108(3):597-601. doi: 10.1038/bjc.2012.507. Epub 2012 Nov 20.
• [13] SPRED2 deficiency elicits cardiac arrhythmias and premature death via impaired autophagy.J Mol Cell Cardiol. 2019 Apr;129:13-26. doi: 10.1016/j.yjmcc.2019.01.023. Epub 2019 Feb 13.
• [14] Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice.Front Immunol. 2019 Jan 22;10:17. doi: 10.3389/fimmu.2019.00017. eCollection 2019.
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• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] 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.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] 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.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [33] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.