Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT58PUEN)

• DOT Name: Protein phosphatase 3 catalytic subunit alpha (PPP3CA)
• Synonyms: EC 3.1.3.16; CAM-PRP catalytic subunit; Calcineurin A alpha; Calmodulin-dependent calcineurin A subunit alpha isoform; CNA alpha; Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
• Gene Name: PPP3CA
• Related Disease:
  Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development
  Epileptic encephalopathy, infantile or early childhood, 1
  Autosomal dominant non-syndromic intellectual disability
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: PP2BA_HUMAN
• PDB ID: 1AUI; 1M63; 1MF8; 2JOG; 2JZI; 2P6B; 2R28; 2W73; 3LL8; 4F0Z; 4Q5U; 5C1V; 5SVE; 6NUC; 6NUF; 6NUU; 6UUQ
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MSEPKAIDPKLSTTDRVVKAVPFPPSHRLTAKEVFDNDGKPRVDILKAHLMKEGRLEESV
  ALRIITEGASILRQEKNLLDIDAPVTVCGDIHGQFFDLMKLFEVGGSPANTRYLFLGDYV
  DRGYFSIECVLYLWALKILYPKTLFLLRGNHECRHLTEYFTFKQECKIKYSERVYDACMD
  AFDCLPLAALMNQQFLCVHGGLSPEINTLDDIRKLDRFKEPPAYGPMCDILWSDPLEDFG
  NEKTQEHFTHNTVRGCSYFYSYPAVCEFLQHNNLLSILRAHEAQDAGYRMYRKSQTTGFP
  SLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEK
  VTEMLVNVLNICSDDELGSEEDGFDGATAAARKEVIRNKIRAIGKMARVFSVLREESESV
  LTLKGLTPTGMLPSGVLSGGKQTLQSATVEAIEADEAIKGFSPQHKITSFEEAKGLDRIN
  ERMPPRRDAMPSDANLNSINKALTSETNGTDSNGSNSSNIQ
• Function: Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals. Many of the substrates contain a PxIxIT motif and/or a LxVP motif. In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation. In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion. Positively regulates the CACNA1B/CAV2.2-mediated Ca(2+) release probability at hippocampal neuronal soma and synaptic terminals. Dephosphorylates heat shock protein HSPB1. Dephosphorylates and activates transcription factor NFATC1. In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32. May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins. Dephosphorylates transcription factor TFEB at 'Ser-211' following Coxsackievirus B3 infection, promoting nuclear translocation. Required for postnatal development of the nephrogenic zone and superficial glomeruli in the kidneys, cell cycle homeostasis in the nephrogenic zone, and ultimately normal kidney function. Plays a role in intracellular AQP2 processing and localization to the apical membrane in the kidney, may thereby be required for efficient kidney filtration. Required for secretion of salivary enzymes amylase, peroxidase, lysozyme and sialic acid via formation of secretory vesicles in the submandibular glands. Required for calcineurin activity and homosynaptic depotentiation in the hippocampus. Required for normal differentiation and survival of keratinocytes and therefore required for epidermis superstructure formation. Positively regulates osteoblastic bone formation, via promotion of osteoblast differentiation. Positively regulates osteoclast differentiation, potentially via NFATC1 signaling. May play a role in skeletal muscle fiber type specification, potentially via NFATC1 signaling. Negatively regulates MAP3K14/NIK signaling via inhibition of nuclear translocation of the transcription factors RELA and RELB. Required for antigen-specific T-cell proliferation response. Dephosphorylates KLHL3, promoting the interaction between KLHL3 and WNK4 and subsequent degradation of WNK4. Negatively regulates SLC9A1 activity.
• Tissue Specificity: Expressed in keratinocytes (at protein level) . Expressed in lymphoblasts (at protein level) .
• 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)
  DARPP-32 events (R-HSA-180024)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development	DISHMSY8	Strong	Autosomal dominant	[1]
Epileptic encephalopathy, infantile or early childhood, 1	DISK4S4C	Strong	Autosomal dominant	[2]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Protein phosphatase 3 catalytic subunit alpha (PPP3CA) affects the response to substance of Methotrexate.	[26]

1 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 Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[14]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[23]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[24]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[17]
Staurosporine	DM0E9BR	Investigative	Staurosporine increases the cleavage of Protein phosphatase 3 catalytic subunit alpha (PPP3CA).	[25]

References

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• [2] Use of a targeted, combinatorial next-generation sequencing approach for the study of bicuspid aortic valve. BMC Med Genomics. 2014 Sep 26;7:56. doi: 10.1186/1755-8794-7-56.
• [3] 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.
• [4] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [5] 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.
• [6] 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.
• [7] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [8] 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.
• [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] Arsenic trioxide initiates ER stress responses, perturbs calcium signalling and promotes apoptosis in human lens epithelial cells. Exp Eye Res. 2007 Dec;85(6):825-35. doi: 10.1016/j.exer.2007.08.018. Epub 2007 Aug 29.
• [11] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [14] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [15] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. Toxicol In Vitro. 2017 Oct;44:196-205. doi: 10.1016/j.tiv.2017.06.010. Epub 2017 Jun 12.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [23] 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.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [25] Caspase-mediated proteolytic activation of calcineurin in thapsigargin-mediated apoptosis in SH-SY5Y neuroblastoma cells. Arch Biochem Biophys. 2000 Jul 15;379(2):337-43. doi: 10.1006/abbi.2000.1889.
• [26] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.