Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB)
• Synonyms: EC 3.1.3.16; CAM-PRP catalytic subunit; Calmodulin-dependent calcineurin A subunit beta isoform; CNA beta
• Gene Name: PPP3CB
• Related Disease:
  Aortic valve stenosis
  Bipolar disorder
  Cornea plana
  Neoplasm
  Pancreatitis
  Schizophrenia
  Wilson disease
  Neuroblastoma
• UniProt ID: PP2BB_HUMAN
• PDB ID: 4OR9; 4ORA; 4ORC
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MAAPEPARAAPPPPPPPPPPPGADRVVKAVPFPPTHRLTSEEVFDLDGIPRVDVLKNHLV
  KEGRVDEEIALRIINEGAAILRREKTMIEVEAPITVCGDIHGQFFDLMKLFEVGGSPANT
  RYLFLGDYVDRGYFSIECVLYLWVLKILYPSTLFLLRGNHECRHLTEYFTFKQECKIKYS
  ERVYEACMEAFDSLPLAALLNQQFLCVHGGLSPEIHTLDDIRRLDRFKEPPAFGPMCDLL
  WSDPSEDFGNEKSQEHFSHNTVRGCSYFYNYPAVCEFLQNNNLLSIIRAHEAQDAGYRMY
  RKSQTTGFPSLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFT
  WSLPFVGEKVTEMLVNVLSICSDDELMTEGEDQFDGSAAARKEIIRNKIRAIGKMARVFS
  VLREESESVLTLKGLTPTGMLPSGVLAGGRQTLQSATVEAIEAEKAIRGFSPPHRICSFE
  EAKGLDRINERMPPRKDAVQQDGFNSLNTAHATENHGTGNHTAQ
• Function: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Dephosphorylates TFEB in response to lysosomal Ca(2+) release, resulting in TFEB nuclear translocation and stimulation of lysosomal biogenesis. Dephosphorylates and activates transcription factor NFATC1. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32. Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB. May play a role in skeletal muscle fiber type specification.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Oocyte meiosis (hsa04114)
  Cellular senescence (hsa04218)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  VEGF sig.ling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  C-type lectin receptor sig.ling pathway (hsa04625)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Long-term potentiation (hsa04720)
  Glutamatergic sy.pse (hsa04724)
  Dopaminergic sy.pse (hsa04728)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Tuberculosis (hsa05152)
  Human cytomegalovirus infection (hsa05163)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Calcineurin activates NFAT (R-HSA-2025928)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  Ca2+ pathway (R-HSA-4086398)
  CLEC7A (Dectin-1) induces NFAT activation (R-HSA-5607763)
  ROBO receptors bind AKAP5 (R-HSA-9010642)
  DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic valve stenosis	DISW7AQ9	Strong	Altered Expression	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Cornea plana	DISE38HI	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[6]
Wilson disease	DISVS9H7	Strong	Biomarker	[7]
Neuroblastoma	DISVZBI4	Disputed	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[17]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[19]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[23]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[24]
PHTPP	DMBHKAV	Investigative	PHTPP increases the expression of Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform (PPP3CB).	[25]

References

• [1] Upregulation of myocardial estrogen receptors in human aortic stenosis.Circulation. 2004 Nov 16;110(20):3270-5. doi: 10.1161/01.CIR.0000147610.41984.E8. Epub 2004 Nov 8.
• [2] A network of synaptic genes associated with schizophrenia and bipolar disorder.Schizophr Res. 2016 Apr;172(1-3):68-74. doi: 10.1016/j.schres.2016.02.012. Epub 2016 Feb 15.
• [3] Dominantly and recessively inherited cornea plana congenita map to the same small region of chromosome 12.Genome Res. 1996 Apr;6(4):249-54. doi: 10.1101/gr.6.4.249.
• [4] PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma.Mol Carcinog. 2019 Mar;58(3):426-435. doi: 10.1002/mc.22939. Epub 2018 Dec 13.
• [5] Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-B, Calcium Signaling, and Calcineurin.Gastroenterology. 2015 Sep;149(3):753-64.e11. doi: 10.1053/j.gastro.2015.05.004. Epub 2015 May 14.
• [6] Comparative Analysis of Gene Expression Profiles Involved in Calcium Signaling Pathways Using the NLVH Animal Model of Schizophrenia.J Mol Neurosci. 2018 Jan;64(1):111-116. doi: 10.1007/s12031-017-1013-y. Epub 2017 Dec 6.
• [7] The early molecular processes underlying the neurological manifestations of an animal model of Wilson's disease.Metallomics. 2013 May;5(5):532-40. doi: 10.1039/c3mt20243g. Epub 2013 Mar 21.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [14] 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.
• [15] Arsenic trioxide induces endoplasmic reticulum stress-related events in neutrophils. Int Immunopharmacol. 2010 Apr;10(4):508-12. doi: 10.1016/j.intimp.2010.01.013. Epub 2010 Feb 4.
• [16] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [17] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [18] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [19] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [20] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [24] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.
• [25] Low doses of BPF-induced hypertrophy in cardiomyocytes derived from human embryonic stem cells via disrupting the mitochondrial fission upon the interaction between ER and calcineurin A-DRP1 signaling pathway. Cell Biol Toxicol. 2022 Jun;38(3):409-426. doi: 10.1007/s10565-021-09615-y. Epub 2021 May 22.