Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW4N3FV)

• DOT Name: Protein scribble homolog (SCRIB)
• Synonyms: Scribble; hScrib; Protein LAP4
• Gene Name: SCRIB
• Related Disease:
  Pneumocystis pneumonia
  8q24.3 microdeletion syndrome
  Anencephaly
  Autosomal dominant polycystic kidney disease
  Breast neoplasm
  Coloboma
  Colonic neoplasm
  Familial adenomatous polyposis
  Hepatocellular carcinoma
  Isolated congenital microcephaly
  Neoplasm
  Neural tube defect
  Neural tube defects, susceptibility to
  Advanced cancer
  Endometrial carcinoma
  Lung cancer
  Lung carcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Autism spectrum disorder
  Autosomal recessive polycystic kidney disease
• UniProt ID: SCRIB_HUMAN
• PDB ID: 1UJU ; 1WHA ; 1X5Q ; 2W4F ; 4WYT ; 4WYU ; 5VWC ; 5VWI ; 5VWK ; 6EEY ; 6ESP ; 6MS1 ; 6MTU ; 6MTV ; 6MYE ; 6MYF ; 6XA6 ; 6XA7 ; 6XA8 ; 7JO7 ; 7QRS ; 7QRT ; 7QS8 ; 7QS9 ; 7QSA ; 7QSB ; 7QTO ; 7QTP ; 7QTU ; 8B82 ; 8B87 ; 8B8O ; 8B9T ; 8BIA ; 8BJ0
• Pfam ID: PF00560 ; PF13855 ; PF00595
• Sequence:
  MLKCIPLWRCNRHVESVDKRHCSLQAVPEEIYRYSRSLEELLLDANQLRELPKPFFRLLN
  LRKLGLSDNEIQRLPPEVANFMQLVELDVSRNDIPEIPESIKFCKALEIADFSGNPLSRL
  PDGFTQLRSLAHLALNDVSLQALPGDVGNLANLVTLELRENLLKSLPASLSFLVKLEQLD
  LGGNDLEVLPDTLGALPNLRELWLDRNQLSALPPELGNLRRLVCLDVSENRLEELPAELG
  GLVLLTDLLLSQNLLRRLPDGIGQLKQLSILKVDQNRLCEVTEAIGDCENLSELILTENL
  LMALPRSLGKLTKLTNLNVDRNHLEALPPEIGGCVALSVLSLRDNRLAVLPPELAHTTEL
  HVLDVAGNRLQSLPFALTHLNLKALWLAENQAQPMLRFQTEDDARTGEKVLTCYLLPQQP
  PPSLEDAGQQGSLSETWSDAPPSRVSVIQFLEAPIGDEDAEEAAAEKRGLQRRATPHPSE
  LKVMKRSIEGRRSEACPCQPDSGSPLPAEEEKRLSAESGLSEDSRPSASTVSEAEPEGPS
  AEAQGGSQQEATTAGGEEDAEEDYQEPTVHFAEDALLPGDDREIEEGQPEAPWTLPGGRQ
  RLIRKDTPHYKKHFKISKLPQPEAVVALLQGMQPDGEGPVAPGGWHNGPHAPWAPRAQKE
  EEEEEEGSPQEEEEEEEEENRAEEEEASTEEEDKEGAVVSAPSVKGVSFDQANNLLIEPA
  RIEEEELTLTILRQTGGLGISIAGGKGSTPYKGDDEGIFISRVSEEGPAARAGVRVGDKL
  LEVNGVALQGAEHHEAVEALRGAGTAVQMRVWRERMVEPENAVTITPLRPEDDYSPRERR
  GGGLRLPLLPPESPGPLRQRHVACLARSERGLGFSIAGGKGSTPYRAGDAGIFVSRIAEG
  GAAHRAGTLQVGDRVLSINGVDVTEARHDHAVSLLTAASPTIALLLEREAGGPLPPSPLP
  HSSPPTAAVATTSITTATPGVPGLPSLAPSLLAAALEGPYPVEEIRLPRAGGPLGLSIVG
  GSDHSSHPFGVQEPGVFISKVLPRGLAARSGLRVGDRILAVNGQDVRDATHQEAVSALLR
  PCLELSLLVRRDPAPPGLRELCIQKAPGERLGISIRGGARGHAGNPRDPTDEGIFISKVS
  PTGAAGRDGRLRVGLRLLEVNQQSLLGLTHGEAVQLLRSVGDTLTVLVCDGFEASTDAAL
  EVSPGVIANPFAAGIGHRNSLESISSIDRELSPEGPGKEKELPGQTLHWGPEATEAAGRG
  LQPLKLDYRALAAVPSAGSVQRVPSGAAGGKMAESPCSPSGQQPPSPPSPDELPANVKQA
  YRAFAAVPTSHPPEDAPAQPPTPGPAASPEQLSFRERQKYFELEVRVPQAEGPPKRVSLV
  GADDLRKMQEEEARKLQQKRAQMLREAAEAGAEARLALDGETLGEEEQEDEQPPWASPSP
  TSRQSPASPPPLGGGAPVRTAKAERRHQERLRVQSPEPPAPERALSPAELRALEAEKRAL
  WRAARMKSLEQDALRAQMVLSRSQEGRGTRGPLERLAEAPSPAPTPSPTPVEDLGPQTST
  SPGRLSPDFAEELRSLEPSPSPGPQEEDGEVALVLLGRPSPGAVGPEDVALCSSRRPVRP
  GRRGLGPVPS
• Function: Scaffold protein involved in different aspects of polarized cell differentiation regulating epithelial and neuronal morphogenesis and T-cell polarization. Via its interaction with CRTAM, required for the late phase polarization of a subset of CD4+ T-cells, which in turn regulates TCR-mediated proliferation and IFNG and IL22 production. Most probably functions in the establishment of apico-basal cell polarity. May function in cell proliferation regulating progression from G1 to S phase and as a positive regulator of apoptosis for instance during acinar morphogenesis of the mammary epithelium. May also function in cell migration and adhesion and hence regulate cell invasion through MAPK signaling. May play a role in exocytosis and in the targeting of synaptic vesicles to synapses. Functions as an activator of Rac GTPase activity.
• Tissue Specificity: Expressed in kidney, skeletal muscles, liver, lung, breast, intestine, placenta and skin mainly in epithelial cells (at protein level).
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOJ GTPase cycle (R-HSA-9013409)
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  Asymmetric localization of PCP proteins (R-HSA-4608870)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pneumocystis pneumonia	DISFSOM3	Definitive	Genetic Variation	[1]
8q24.3 microdeletion syndrome	DISI3CFH	Strong	Genetic Variation	[2]
Anencephaly	DISIYW6T	Strong	Genetic Variation	[3]
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Coloboma	DISP39N5	Strong	Genetic Variation	[2]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Neural tube defect	DIS5J95E	Strong	Biomarker	[1]
Neural tube defects, susceptibility to	DISHA84K	Strong	Genetic Variation	[10]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[11]
Endometrial carcinoma	DISXR5CY	moderate	Altered Expression	[12]
Lung cancer	DISCM4YA	moderate	Biomarker	[13]
Lung carcinoma	DISTR26C	moderate	Biomarker	[13]
Prostate cancer	DISF190Y	moderate	Biomarker	[12]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[12]
Prostate neoplasm	DISHDKGQ	moderate	Altered Expression	[12]
Autism spectrum disorder	DISXK8NV	Limited	Autosomal dominant	[14]
Autosomal recessive polycystic kidney disease	DISPUS40	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein scribble homolog (SCRIB).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of Protein scribble homolog (SCRIB).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein scribble homolog (SCRIB).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Protein scribble homolog (SCRIB).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein scribble homolog (SCRIB).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein scribble homolog (SCRIB).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein scribble homolog (SCRIB).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein scribble homolog (SCRIB).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein scribble homolog (SCRIB).	[19]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Protein scribble homolog (SCRIB).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein scribble homolog (SCRIB).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein scribble homolog (SCRIB).	[25]

References

• [1] Scribble1 plays an important role in the pathogenesis of neural tube defects through its mediating effect of Par-3 and Vangl1/2 localization.Hum Mol Genet. 2017 Jun 15;26(12):2307-2320. doi: 10.1093/hmg/ddx122.
• [2] PUF60-SCRIB fusion transcript in a patient with 8q24.3 microdeletion and atypical Verheij syndrome.Eur J Med Genet. 2019 Dec;62(12):103587. doi: 10.1016/j.ejmg.2018.11.021. Epub 2018 Nov 23.
• [3] Digenic variants of planar cell polarity genes in human neural tube defect patients.Mol Genet Metab. 2018 May;124(1):94-100. doi: 10.1016/j.ymgme.2018.03.005. Epub 2018 Mar 18.
• [4] Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway.FASEB J. 2018 Aug;32(8):4394-4407. doi: 10.1096/fj.201701376RR. Epub 2018 Mar 12.
• [5] Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma.Cell. 2008 Nov 28;135(5):865-78. doi: 10.1016/j.cell.2008.09.045.
• [6] Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression.Int J Cancer. 2006 Sep 15;119(6):1285-90. doi: 10.1002/ijc.21982.
• [7] Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli.Genes Cells. 2006 Apr;11(4):453-64. doi: 10.1111/j.1365-2443.2006.00954.x.
• [8] Identification of potential driver genes in human liver carcinoma by genomewide screening.Cancer Res. 2009 May 1;69(9):4059-66. doi: 10.1158/0008-5472.CAN-09-0164. Epub 2009 Apr 14.
• [9] The Tumor Suppressor SCRIB is a Negative Modulator of the Wnt/-Catenin Signaling Pathway.Proteomics. 2019 Nov;19(21-22):e1800487. doi: 10.1002/pmic.201800487. Epub 2019 Oct 20.
• [10] Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum Mutat. 2012 Feb;33(2):440-7. doi: 10.1002/humu.21662. Epub 2011 Dec 20.
• [11] Molecular changes in appearance of a cancer cell among normal HEK293T cells.J Biosci Bioeng. 2017 Mar;123(3):281-286. doi: 10.1016/j.jbiosc.2016.09.012. Epub 2016 Oct 21.
• [12] SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia.J Clin Invest. 2011 Nov;121(11):4257-67. doi: 10.1172/JCI58509. Epub 2011 Oct 3.
• [13] Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo.Oncogene. 2014 Nov 27;33(48):5523-33. doi: 10.1038/onc.2013.498. Epub 2013 Nov 25.
• [14] 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.
• [15] Atmin modulates Pkhd1 expression and may mediate Autosomal Recessive Polycystic Kidney Disease (ARPKD) through altered non-canonical Wnt/Planar Cell Polarity (PCP) signalling.Biochim Biophys Acta Mol Basis Dis. 2019 Feb 1;1865(2):378-390. doi: 10.1016/j.bbadis.2018.11.003. Epub 2018 Nov 7.
• [16] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [17] 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.
• [18] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [19] 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.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] 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.
• [22] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [23] 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.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.