Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2VK9N0)

• DOT Name: Protein sprouty homolog 4 (SPRY4)
• Synonyms: Spry-4
• Gene Name: SPRY4
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Androgen insensitivity syndrome
  Brain cancer
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Endometrium adenocarcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Germ cell tumor
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Polycythemia vera
  Prostate neoplasm
  Schizophrenia
  Gastrointestinal stromal tumour
  Lung cancer
  Lung carcinoma
  Rhabdomyosarcoma
  Hypogonadotropic hypogonadism
  Kallmann syndrome
  Melanoma
  Hypogonadotropic hypogonadism 17 with or without anosmia
  Neoplasm
  Testicular germ cell tumor
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: SPY4_HUMAN
• PDB ID: 3BUN
• Pfam ID: PF05210
• Sequence:
  MEPPIPQSAPLTPNSVMVQPLLDSRMSHSRLQHPLTILPIDQVKTSHVENDYIDNPSLAL
  TTGPKRTRGGAPELAPTPARCDQDVTHHWISFSGRPSSVSSSSSTSSDQRLLDHMAPPPV
  ADQASPRAVRIQPKVVHCQPLDLKGPAVPPELDKHFLLCEACGKCKCKECASPRTLPSCW
  VCNQECLCSAQTLVNYGTCMCLVQGIFYHCTNEDDEGSCADHPCSCSRSNCCARWSFMGA
  LSVVLPCLLCYLPATGCVKLAQRGYDRLRRPGCRCKHTNSVICKAASGDAKTSRPDKPF
• Function: Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1. Represses integrin-mediated cell spreading via inhibition of TESK1-mediated phosphorylation of cofilin.

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Androgen insensitivity syndrome	DISUZBBO	Strong	Altered Expression	[3]
Brain cancer	DISBKFB7	Strong	Altered Expression	[2]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Endometrium adenocarcinoma	DISY6744	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Germ cell tumor	DIS62070	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[14]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[8]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[8]
Polycythemia vera	DISB5FPO	Strong	Biomarker	[15]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[16]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[17]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[18]
Lung cancer	DISCM4YA	moderate	Biomarker	[19]
Lung carcinoma	DISTR26C	moderate	Biomarker	[19]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[20]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[21]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[21]
Melanoma	DIS1RRCY	Disputed	Biomarker	[22]
Hypogonadotropic hypogonadism 17 with or without anosmia	DIS1FL1O	Limited	Unknown	[21]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]
Testicular germ cell tumor	DIS5RN24	Limited	Genetic Variation	[23]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[24]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[24]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[24]

21 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 Protein sprouty homolog 4 (SPRY4).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein sprouty homolog 4 (SPRY4).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein sprouty homolog 4 (SPRY4).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein sprouty homolog 4 (SPRY4).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Protein sprouty homolog 4 (SPRY4).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Protein sprouty homolog 4 (SPRY4).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein sprouty homolog 4 (SPRY4).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein sprouty homolog 4 (SPRY4).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein sprouty homolog 4 (SPRY4).	[33]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein sprouty homolog 4 (SPRY4).	[34]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Protein sprouty homolog 4 (SPRY4).	[35]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Protein sprouty homolog 4 (SPRY4).	[33]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Protein sprouty homolog 4 (SPRY4).	[36]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Protein sprouty homolog 4 (SPRY4).	[37]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Protein sprouty homolog 4 (SPRY4).	[38]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein sprouty homolog 4 (SPRY4).	[39]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Protein sprouty homolog 4 (SPRY4).	[40]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Protein sprouty homolog 4 (SPRY4).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein sprouty homolog 4 (SPRY4).	[44]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein sprouty homolog 4 (SPRY4).	[45]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein sprouty homolog 4 (SPRY4).	[46]

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 increases the methylation of Protein sprouty homolog 4 (SPRY4).	[41]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Protein sprouty homolog 4 (SPRY4).	[43]

References

• [1] Clinical impact of KMT2C and SPRY4 expression levels in intensively treated younger adult acute myeloid leukemia patients.Eur J Haematol. 2017 Dec;99(6):544-552. doi: 10.1111/ejh.12972. Epub 2017 Oct 13.
• [2] Sprouty3 and Sprouty4, Two Members of a Family Known to Inhibit FGF-Mediated Signaling, Exert Opposing Roles on Proliferation and Migration of Glioblastoma-Derived Cells.Cells. 2019 Aug 1;8(8):808. doi: 10.3390/cells8080808.
• [3] SPRY4 is responsible for pathogenesis of adolescent idiopathic scoliosis by contributing to osteogenic differentiation and melatonin response of bone marrow-derived mesenchymal stem cells.Cell Death Dis. 2019 Oct 23;10(11):805. doi: 10.1038/s41419-019-1949-7.
• [4] MicroRNA?81 serves an oncogenic role in breast cancer via the inhibition of SPRY4.Mol Med Rep. 2018 Dec;18(6):5603-5613. doi: 10.3892/mmr.2018.9572. Epub 2018 Oct 22.
• [5] Long non-coding RNA SPRY4-IT1 promotes epithelial-mesenchymal transition of cervical cancer by regulating the miR-101-3p/ZEB1 axis.Biosci Rep. 2019 Jun 4;39(6):BSR20181339. doi: 10.1042/BSR20181339. Print 2019 Jun 28.
• [6] Lower Expression of SPRY4 Predicts a Poor Prognosis and Regulates Cell Proliferation in Colorectal Cancer.Cell Physiol Biochem. 2016;40(6):1433-1442. doi: 10.1159/000453195. Epub 2016 Dec 20.
• [7] SPRY4-mediated ERK1/2 signaling inhibition abolishes 17-estradiol-induced cell growth in endometrial adenocarcinoma cell.Gynecol Endocrinol. 2014 Aug;30(8):600-4. doi: 10.3109/09513590.2014.912264. Epub 2014 May 8.
• [8] Knockdown of SPRY4 and SPRY4-IT1 inhibits cell growth and phosphorylation of Akt in human testicular germ cell tumours.Sci Rep. 2018 Feb 6;8(1):2462. doi: 10.1038/s41598-018-20846-8.
• [9] H3K27 acetylation activated-long non-coding RNA CCAT1 affects cell proliferation and migration by regulating SPRY4 and HOXB13 expression in esophageal squamous cell carcinoma.Nucleic Acids Res. 2017 Apr 7;45(6):3086-3101. doi: 10.1093/nar/gkw1247.
• [10] Variants in BAK1, SPRY4, and GAB2 are associated with pediatric germ cell tumors: A report from the children's oncology group.Genes Chromosomes Cancer. 2017 Jul;56(7):548-558. doi: 10.1002/gcc.22457. Epub 2017 Apr 4.
• [11] miR-1908 as a novel prognosis marker of glioma via promoting malignant phenotype and modulating SPRY4/RAF1 axis.Oncol Rep. 2017 Nov;38(5):2717-2726. doi: 10.3892/or.2017.6003. Epub 2017 Sep 26.
• [12] Potential diagnostic value of lncRNA SPRY4-IT1 in hepatocellular carcinoma.Oncol Rep. 2016 Aug;36(2):1085-92. doi: 10.3892/or.2016.4859. Epub 2016 Jun 7.
• [13] Up-regulation of long non-coding RNA SPRY4-IT1 promotes tumor cell migration and invasion in lung adenocarcinoma.Oncotarget. 2017 Apr 7;8(31):51058-51065. doi: 10.18632/oncotarget.16918. eCollection 2017 Aug 1.
• [14] K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer.J Biol Chem. 2017 May 5;292(18):7423-7434. doi: 10.1074/jbc.M116.757906. Epub 2017 Mar 8.
• [15] Sprouty proteins are negative regulators of interferon (IFN) signaling and IFN-inducible biological responses.J Biol Chem. 2012 Dec 7;287(50):42352-60. doi: 10.1074/jbc.M112.400721. Epub 2012 Oct 16.
• [16] Sprouty4, a suppressor of tumor cell motility, is down regulated by DNA methylation in human prostate cancer.Prostate. 2006 May 1;66(6):613-24. doi: 10.1002/pros.20353.
• [17] MicroRNA-382 expression is elevated in the olfactory neuroepithelium of schizophrenia patients.Neurobiol Dis. 2013 Jul;55:1-10. doi: 10.1016/j.nbd.2013.03.011. Epub 2013 Mar 29.
• [18] Kit K641E oncogene up-regulates Sprouty homolog 4 and trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours.J Cell Mol Med. 2009 Aug;13(8A):1536-48. doi: 10.1111/j.1582-4934.2009.00768.x. Epub 2009 May 19.
• [19] Oncogenic microRNA-411 promotes lung carcinogenesis by directly targeting suppressor genes SPRY4 and TXNIP.Oncogene. 2019 Mar;38(11):1892-1904. doi: 10.1038/s41388-018-0534-3. Epub 2018 Nov 2.
• [20] Autoregulatory loop between TGF-1/miR-411-5p/SPRY4 and MAPK pathway in rhabdomyosarcoma modulates proliferation and differentiation.Cell Death Dis. 2015 Aug 20;6(8):e1859. doi: 10.1038/cddis.2015.225.
• [21] Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet. 2013 May 2;92(5):725-43. doi: 10.1016/j.ajhg.2013.04.008.
• [22] High-resolution population structure and runs of homozygosity reveal the genetic architecture of complex traits in the Lipizzan horse.BMC Genomics. 2019 Mar 5;20(1):174. doi: 10.1186/s12864-019-5564-x.
• [23] Genes associated with testicular germ cell tumors and testicular dysgenesis in patients with testicular microlithiasis.Asian J Androl. 2018 Nov-Dec;20(6):593-599. doi: 10.4103/aja.aja_54_18.
• [24] LncRNA SPRY4-IT was concerned with the poor prognosis and contributed to the progression of thyroid cancer.Cancer Gene Ther. 2018 Feb;25(1-2):39-46. doi: 10.1038/s41417-017-0003-0. Epub 2017 Dec 12.
• [25] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [26] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [27] 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.
• [28] 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.
• [29] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [32] 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.
• [33] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [34] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [35] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [36] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [37] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [38] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [39] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [40] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [41] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [42] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [43] 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.
• [44] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [45] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [46] 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.