Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6A63TX)

• DOT Name: Sushi repeat-containing protein SRPX2 (SRPX2)
• Synonyms: Sushi-repeat protein upregulated in leukemia
• Gene Name: SRPX2
• Related Disease:
  Matthew-Wood syndrome
  Pancreatic cancer
  Advanced cancer
  Brain disease
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epilepsy
  Esophageal squamous cell carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Language disorder
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Carcinoma
  Intellectual disability
  Pancreatic ductal carcinoma
  Rolandic epilepsy-speech dyspraxia syndrome
  Apraxia
  Cognitive impairment
  Neoplasm
  Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked
  Bilateral perisylvian polymicrogyria
  Neurodevelopmental disorder
  Polymicrogyria, bilateral perisylvian, X-linked
• UniProt ID: SRPX2_HUMAN
• Pfam ID: PF13778 ; PF02494 ; PF00084
• Sequence:
  MASQLTQRGALFLLFFLTPAVTPTWYAGSGYYPDESYNEVYAEEVPQAPALDYRVPRWCY
  TLNIQDGEATCYSPKGGNYHSSLGTRCELSCDRGFRLIGRRSVQCLPSRRWSGTAYCRQM
  RCHALPFITSGTYTCTNGVLLDSRCDYSCSSGYHLEGDRSRICMEDGRWSGGEPVCVDID
  PPKIRCPHSREKMAEPEKLTARVYWDPPLVKDSADGTITRVTLRGPEPGSHFPEGEHVIR
  YTAYDRAYNRASCKFIVKVQVRRCPTLKPPQHGYLTCTSAGDNYGATCEYHCDGGYDRQG
  TPSRVCQSSRQWSGSPPICAPMKINVNVNSAAGLLDQFYEKQRLLIISAPDPSNRYYKMQ
  ISMLQQSTCGLDLRHVTIIELVGQPPQEVGRIREQQLSANIIEELRQFQRLTRSYFNMVL
  IDKQGIDRDRYMEPVTPEEIFTFIDDYLLSNQELTQRREQRDICE
• Function: Acts as a ligand for the urokinase plasminogen activator surface receptor. Plays a role in angiogenesis by inducing endothelial cell migration and the formation of vascular network (cords). Involved in cellular migration and adhesion. Increases the phosphorylation levels of FAK. Interacts with and increases the mitogenic activity of HGF. Promotes synapse formation. May have a role in the perisylvian region, critical for language and cognitive development.
• Tissue Specificity: Expressed in neurons of the rolandic area of the brain (at protein level). Highly expressed in the brain, placenta, lung, trachea, uterus, adrenal gland, heart, ovary and placenta. Weakly expressed in the peripheral blood, brain and bone marrow. Expressed in numerous cancer cell lines and in gastrointestinal cancer cells. Higher levels found in colorectal cancers than in normal colonic mucosa.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[1]
Pancreatic cancer	DISJC981	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Epilepsy	DISBB28L	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Language disorder	DISTLKP7	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[7]
Carcinoma	DISH9F1N	moderate	Altered Expression	[11]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[12]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[13]
Rolandic epilepsy-speech dyspraxia syndrome	DISWM45T	Supportive	Autosomal dominant	[12]
Apraxia	DISULX63	Disputed	Biomarker	[12]
Cognitive impairment	DISH2ERD	Disputed	Genetic Variation	[14]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[15]
Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked	DISXL3SJ	Disputed	X-linked	[16]
Bilateral perisylvian polymicrogyria	DISIF9XK	Limited	Genetic Variation	[17]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[6]
Polymicrogyria, bilateral perisylvian, X-linked	DISBKRJ6	Limited	X-linked recessive	[18]

18 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 Sushi repeat-containing protein SRPX2 (SRPX2).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[25]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[26]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[27]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[28]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[29]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[30]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[31]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[32]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[34]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sushi repeat-containing protein SRPX2 (SRPX2).	[37]

1 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 Sushi repeat-containing protein SRPX2 (SRPX2).	[35]

References

• [1] SRPX2 and RAB31 are effective prognostic biomarkers in pancreatic cancer.J Cancer. 2019 Jun 2;10(12):2670-2678. doi: 10.7150/jca.32072. eCollection 2019.
• [2] SRPX2 knockdown inhibits cell proliferation and metastasis and promotes chemosensitivity in esophageal squamous cell carcinoma.Biomed Pharmacother. 2019 Jan;109:671-678. doi: 10.1016/j.biopha.2018.10.042. Epub 2018 Nov 5.
• [3] Molecular evolution of the human SRPX2 gene that causes brain disorders of the Rolandic and Sylvian speech areas.BMC Genet. 2007 Oct 18;8:72. doi: 10.1186/1471-2156-8-72.
• [4] SRPX2 regulates colon cancer cell metabolism by miR-192/215 via PI3K-Akt.Am J Transl Res. 2018 Feb 15;10(2):483-490. eCollection 2018.
• [5] Increased Sushi repeat-containing protein X-linked 2 is associated with progression of colorectal cancer.Med Oncol. 2015 Apr;32(4):99. doi: 10.1007/s12032-015-0548-4. Epub 2015 Mar 4.
• [6] Exploring the association between SRPX2 variants and neurodevelopment: How causal is it?.Gene. 2019 Feb 15;685:50-54. doi: 10.1016/j.gene.2018.10.067. Epub 2018 Oct 25.
• [7] Impact of overexpression of Sushi repeat-containing protein X-linked 2 gene on outcomes of gastric cancer.J Surg Oncol. 2014 Jun;109(8):836-40. doi: 10.1002/jso.23602. Epub 2014 Apr 2.
• [8] SRPX2, an independent prognostic marker, promotes cell migration and invasion in hepatocellular carcinoma.Biomed Pharmacother. 2017 Sep;93:398-405. doi: 10.1016/j.biopha.2017.06.075. Epub 2017 Jun 24.
• [9] The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice.Science. 2013 Nov 22;342(6161):987-91. doi: 10.1126/science.1245079. Epub 2013 Oct 31.
• [10] Knockdown of SRPX2 inhibits the proliferation, migration, and invasion of prostate cancer cells through the PI3K/Akt/mTOR signaling pathway.J Biochem Mol Toxicol. 2018 Dec 9:e22237. doi: 10.1002/jbt.22237. Online ahead of print.
• [11] O-glycans truncation modulates gastric cancer cell signaling and transcription leading to a more aggressive phenotype.EBioMedicine. 2019 Feb;40:349-362. doi: 10.1016/j.ebiom.2019.01.017. Epub 2019 Jan 17.
• [12] SRPX2 mutations in disorders of language cortex and cognition. Hum Mol Genet. 2006 Apr 1;15(7):1195-207. doi: 10.1093/hmg/ddl035. Epub 2006 Feb 23.
• [13] SRPX2 promotes cell migration and invasion via FAK dependent pathway in pancreatic cancer.Int J Clin Exp Pathol. 2015 May 1;8(5):4791-8. eCollection 2015.
• [14] Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.J Med Genet. 2014 Nov;51(11):724-36. doi: 10.1136/jmedgenet-2014-102554. Epub 2014 Aug 28.
• [15] High SRPX2 protein expression predicts unfavorable clinical outcome in patients with prostate cancer.Onco Targets Ther. 2018 May 28;11:3149-3157. doi: 10.2147/OTT.S158820. eCollection 2018.
• [16] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [17] Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex.Hum Mol Genet. 2010 Dec 15;19(24):4848-60. doi: 10.1093/hmg/ddq415. Epub 2010 Sep 21.
• [18] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [21] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] 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.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [27] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [28] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [29] 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.
• [30] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [31] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [32] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [33] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [34] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [35] 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.
• [36] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.