Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7E6V9B)

• DOT Name: Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C)
• Synonyms: Protein phosphatase subunit G5PR; Rhabdomyosarcoma antigen MU-RMS-40.6A/6C
• Gene Name: PPP2R3C
• Related Disease:
  46,XY complete gonadal dysgenesis
  Atopic dermatitis
  Gonadal dysgenesis
  Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy
  Insomnia
  Turner syndrome
  Ankylosing spondylitis
  Crohn disease
  Psoriasis
  Sclerosing cholangitis
  Spermatogenic failure 36
  Ulcerative colitis
• UniProt ID: P2R3C_HUMAN
• Pfam ID: PF17958
• Sequence:
  MDWKEVLRRRLATPNTCPNKKKSEQELKDEEMDLFTKYYSEWKGGRKNTNEFYKTIPRFY
  YRLPAEDEVLLQKLREESRAVFLQRKSRELLDNEELQNLWFLLDKHQTPPMIGEEAMINY
  ENFLKVGEKAGAKCKQFFTAKVFAKLLHTDSYGRISIMQFFNYVMRKVWLHQTRIGLSLY
  DVAGQGYLRESDLENYILELIPTLPQLDGLEKSFYSFYVCTAVRKFFFFLDPLRTGKIKI
  QDILACSFLDDLLELRDEELSKESQETNWFSAPSALRVYGQYLNLDKDHNGMLSKEELSR
  YGTATMTNVFLDRVFQECLTYDGEMDYKTYLDFVLALENRKEPAALQYIFKLLDIENKGY
  LNVFSLNYFFRAIQELMKIHGQDPVSFQDVKDEIFDMVKPKDPLKISLQDLINSNQGDTV
  TTILIDLNGFWTYENREALVANDSENSADLDDT
• Function: May regulate MCM3AP phosphorylation through phosphatase recruitment. May act as a negative regulator of ABCB1 expression and function through the dephosphorylation of ABCB1 by TFPI2/PPP2R3C complex. May play a role in the activation-induced cell death of B-cells.
• Tissue Specificity: Ubiquitously expressed in brain and other tissues.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  T cell receptor sig.ling pathway (hsa04660)
  Dopaminergic sy.pse (hsa04728)
  Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XY complete gonadal dysgenesis	DISLF3LT	Strong	Genetic Variation	[1]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[2]
Gonadal dysgenesis	DISIL2ZI	Strong	Genetic Variation	[1]
Gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy	DISIKKAL	Strong	Autosomal recessive	[3]
Insomnia	DIS0AFR7	Strong	Biomarker	[4]
Turner syndrome	DIS2035C	Strong	Genetic Variation	[1]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[5]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[5]
Psoriasis	DIS59VMN	Limited	Genetic Variation	[5]
Sclerosing cholangitis	DIS7GZNB	Limited	Genetic Variation	[5]
Spermatogenic failure 36	DISM0FV1	Limited	Autosomal dominant	[1]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[5]

8 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 Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[10]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Serine/threonine-protein phosphatase 2A regulatory subunit B'' subunit gamma (PPP2R3C).	[13]

References

• [1] PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans. Eur J Endocrinol. 2019 May 1;180(5):291-309. doi: 10.1530/EJE-19-0067.
• [2] Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.Nat Genet. 2015 Dec;47(12):1449-1456. doi: 10.1038/ng.3424. Epub 2015 Oct 19.
• [3] The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency. Eur J Med Genet. 2018 Jul;61(7):393-398. doi: 10.1016/j.ejmg.2018.02.007. Epub 2018 Feb 22.
• [4] Integrative analysis of genome-wide association study and brain region related enhancer maps identifies biological pathways for insomnia.Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:180-185. doi: 10.1016/j.pnpbp.2018.05.026. Epub 2018 Jun 6.
• [5] Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [12] 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.
• [13] Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
• [14] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.