Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQKC5X2)

• DOT Name: Protein Shroom3 (SHROOM3)
• Synonyms: Shroom-related protein; hShrmL
• Gene Name: SHROOM3
• Related Disease:
  Chronic renal failure
  Advanced cancer
  Cardiomyopathy
  Craniofacial microsomia
  Eosinophilic esophagitis
  Isolated cleft lip
  Type-1/2 diabetes
  Visceral heterotaxy
  Coronary heart disease
  Neural tube defect
  Neoplasm
  Acute myelogenous leukaemia
  Atrial septal defect
  Chronic kidney disease
• UniProt ID: SHRM3_HUMAN
• PDB ID: 6FBB; 6FCP
• Pfam ID: PF08688 ; PF08687 ; PF00595
• Sequence:
  MMRTTEDFHKPSATLNSNTATKGRYIYLEAFLEGGAPWGFTLKGGLEHGEPLIISKVEEG
  GKADTLSSKLQAGDEVVHINEVTLSSSRKEAVSLVKGSYKTLRLVVRRDVCTDPGHADTG
  ASNFVSPEHLTSGPQHRKAAWSGGVKLRLKHRRSEPAGRPHSWHTTKSGEKQPDASMMQI
  SQGMIGPPWHQSYHSSSSTSDLSNYDHAYLRRSPDQCSSQGSMESLEPSGAYPPCHLSPA
  KSTGSIDQLSHFHNKRDSAYSSFSTSSSILEYPHPGISGRERSGSMDNTSARGGLLEGMR
  QADIRYVKTVYDTRRGVSAEYEVNSSALLLQGREARASANGQGYDKWSNIPRGKGVPPPS
  WSQQCPSSLETATDNLPPKVGAPLPPARSDSYAAFRHRERPSSWSSLDQKRLCRPQANSL
  GSLKSPFIEEQLHTVLEKSPENSPPVKPKHNYTQKAQPGQPLLPTSIYPVPSLEPHFAQV
  PQPSVSSNGMLYPALAKESGYIAPQGACNKMATIDENGNQNGSGRPGFAFCQPLEHDLLS
  PVEKKPEATAKYVPSKVHFCSVPENEEDASLKRHLTPPQGNSPHSNERKSTHSNKPSSHP
  HSLKCPQAQAWQAGEDKRSSRLSEPWEGDFQEDHNANLWRRLEREGLGQSLSGNFGKTKS
  AFSSLQNIPESLRRHSSLELGRGTQEGYPGGRPTCAVNTKAEDPGRKAAPDLGSHLDRQV
  SYPRPEGRTGASASFNSTDPSPEEPPAPSHPHTSSLGRRGPGPGSASALQGFQYGKPHCS
  VLEKVSKFEQREQGSQRPSVGGSGFGHNYRPHRTVSTSSTSGNDFEETKAHIRFSESAEP
  LGNGEQHFKNGELKLEEASRQPCGQQLSGGASDSGRGPQRPDARLLRSQSTFQLSSEPER
  EPEWRDRPGSPESPLLDAPFSRAYRNSIKDAQSRVLGATSFRRRDLELGAPVASRSWRPR
  PSSAHVGLRSPEASASASPHTPRERHSVTPAEGDLARPVPPAARRGARRRLTPEQKKRSY
  SEPEKMNEVGIVEEAEPAPLGPQRNGMRFPESSVADRRRLFERDGKACSTLSLSGPELKQ
  FQQSALADYIQRKTGKRPTSAAGCSLQEPGPLRERAQSAYLQPGPAALEGSGLASASSLS
  SLREPSLQPRREATLLPATVAETQQAPRDRSSSFAGGRRLGERRRGDLLSGANGGTRGTQ
  RGDETPREPSSWGARAGKSMSAEDLLERSDVLAGPVHVRSRSSPATADKRQDVLLGQDSG
  FGLVKDPCYLAGPGSRSLSCSERGQEEMLPLFHHLTPRWGGSGCKAIGDSSVPSECPGTL
  DHQRQASRTPCPRPPLAGTQGLVTDTRAAPLTPIGTPLPSAIPSGYCSQDGQTGRQPLPP
  YTPAMMHRSNGHTLTQPPGPRGCEGDGPEHGVEEGTRKRVSLPQWPPPSRAKWAHAARED
  SLPEESSAPDFANLKHYQKQQSLPSLCSTSDPDTPLGAPSTPGRISLRISESVLRDSPPP
  HEDYEDEVFVRDPHPKATSSPTFEPLPPPPPPPPSQETPVYSMDDFPPPPPHTVCEAQLD
  SEDPEGPRPSFNKLSKVTIARERHMPGAAHVVGSQTLASRLQTSIKGSEAESTPPSFMSV
  HAQLAGSLGGQPAPIQTQSLSHDPVSGTQGLEKKVSPDPQKSSEDIRTEALAKEIVHQDK
  SLADILDPDSRLKTTMDLMEGLFPRDVNLLKENSVKRKAIQRTVSSSGCEGKRNEDKEAV
  SMLVNCPAYYSVSAPKAELLNKIKEMPAEVNEEEEQADVNEKKAELIGSLTHKLETLQEA
  KGSLLTDIKLNNALGEEVEALISELCKPNEFDKYRMFIGDLDKVVNLLLSLSGRLARVEN
  VLSGLGEDASNEERSSLYEKRKILAGQHEDARELKENLDRRERVVLGILANYLSEEQLQD
  YQHFVKMKSTLLIEQRKLDDKIKLGQEQVKCLLESLPSDFIPKAGALALPPNLTSEPIPA
  GGCTFSGIFPTLTSPL
• Function: Controls cell shape changes in the neuroepithelium during neural tube closure. Induces apical constriction in epithelial cells by promoting the apical accumulation of F-actin and myosin II, and probably by bundling stress fibers. Induces apicobasal cell elongation by redistributing gamma-tubulin and directing the assembly of robust apicobasal microtubule arrays.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[3]
Craniofacial microsomia	DISYHJ2P	Strong	Genetic Variation	[4]
Eosinophilic esophagitis	DISR8WSB	Strong	Genetic Variation	[5]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[6]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[7]
Visceral heterotaxy	DIS1DV90	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[9]
Neural tube defect	DIS5J95E	moderate	Genetic Variation	[10]
Neoplasm	DISZKGEW	Disputed	Biomarker	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[12]
Atrial septal defect	DISJT76B	Limited	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Limited	Genetic Variation	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein Shroom3 (SHROOM3).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein Shroom3 (SHROOM3).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein Shroom3 (SHROOM3).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein Shroom3 (SHROOM3).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Protein Shroom3 (SHROOM3).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein Shroom3 (SHROOM3).	[19]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein Shroom3 (SHROOM3).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein Shroom3 (SHROOM3).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein Shroom3 (SHROOM3).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein Shroom3 (SHROOM3).	[24]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Protein Shroom3 (SHROOM3).	[25]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Protein Shroom3 (SHROOM3).	[26]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein Shroom3 (SHROOM3).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein Shroom3 (SHROOM3).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein Shroom3 (SHROOM3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Protein Shroom3 (SHROOM3).	[31]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein Shroom3 (SHROOM3).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein Shroom3 (SHROOM3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein Shroom3 (SHROOM3).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein Shroom3 (SHROOM3).	[32]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the phosphorylation of Protein Shroom3 (SHROOM3).	[34]

References

• [1] A catalog of genetic loci associated with kidney function from analyses of a million individuals.Nat Genet. 2019 Jun;51(6):957-972. doi: 10.1038/s41588-019-0407-x. Epub 2019 May 31.
• [2] Coactosin-like protein CLP/Cotl1 suppresses breast cancer growth through activation of IL-24/PERP and inhibition of non-canonical TGF signaling.Oncogene. 2018 Jan 18;37(3):323-331. doi: 10.1038/onc.2017.342. Epub 2017 Sep 18.
• [3] NEXN inhibits GATA4 and leads to atrial septal defects in mice and humans.Cardiovasc Res. 2014 Jul 15;103(2):228-37. doi: 10.1093/cvr/cvu134. Epub 2014 May 27.
• [4] Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia.Nat Commun. 2016 Feb 8;7:10605. doi: 10.1038/ncomms10605.
• [5] Common variants at 5q22 associate with pediatric eosinophilic esophagitis.Nat Genet. 2010 Apr;42(4):289-91. doi: 10.1038/ng.547. Epub 2010 Mar 7.
• [6] Genome-wide meta-analyses of nonsyndromic orofacial clefts identify novel associations between FOXE1 and all orofacial clefts, and TP63 and cleft lip with or without cleft palate.Hum Genet. 2017 Mar;136(3):275-286. doi: 10.1007/s00439-016-1754-7. Epub 2017 Jan 4.
• [7] Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
• [8] SHROOM3 is a novel candidate for heterotaxy identified by whole exome sequencing.Genome Biol. 2011 Sep 21;12(9):R91. doi: 10.1186/gb-2011-12-9-r91.
• [9] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [10] Folic acid modifies the shape of epithelial cells during morphogenesis via a Folr1 and MLCK dependent mechanism.Biol Open. 2019 Jan 22;8(1):bio041160. doi: 10.1242/bio.041160.
• [11] Cortactin overexpression regulates actin-related protein 2/3 complex activity, motility, and invasion in carcinomas with chromosome 11q13 amplification.Cancer Res. 2006 Aug 15;66(16):8017-25. doi: 10.1158/0008-5472.CAN-05-4490.
• [12] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [13] Shroom3 contributes to the maintenance of the glomerular filtration barrier integrity.Genome Res. 2015 Jan;25(1):57-65. doi: 10.1101/gr.182881.114. Epub 2014 Oct 1.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [21] 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.
• [22] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [23] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [24] 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.
• [25] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [26] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [27] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [28] 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.
• [29] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [30] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [31] Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.
• [32] 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.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [34] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.