Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW2QIX9)

• DOT Name: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B)
• Synonyms: PP2A B subunit isoform B'-beta; PP2A B subunit isoform B56-beta; PP2A B subunit isoform PR61-beta; PP2A B subunit isoform R5-beta
• Gene Name: PPP2R5B
• Related Disease:
  Breast neoplasm
  Hyperinsulinemia
  Intellectual disability
  Multiple endocrine neoplasia type 1
• UniProt ID: 2A5B_HUMAN
• Pfam ID: PF01603
• Sequence:
  METKLPPASTPTSPSSPGLSPVPPPDKVDGFSRRSLRRARPRRSHSSSQFRYQSNQQELT
  PLPLLKDVPASELHELLSRKLAQCGVMFDFLDCVADLKGKEVKRAALNELVECVGSTRGV
  LIEPVYPDIIRMISVNIFRTLPPSENPEFDPEEDEPNLEPSWPHLQLVYEFFLRFLESPD
  FQPSVAKRYVDQKFVLMLLELFDSEDPREREYLKTILHRVYGKFLGLRAYIRKQCNHIFL
  RFIYEFEHFNGVAELLEILGSIINGFALPLKTEHKQFLVRVLIPLHSVKSLSVFHAQLAY
  CVVQFLEKDATLTEHVIRGLLKYWPKTCTQKEVMFLGEMEEILDVIEPSQFVKIQEPLFK
  QVARCVSSPHFQVAERALYFWNNEYILSLIEDNCHTVLPAVFGTLYQVSKEHWNQTIVSL
  IYNVLKTFMEMNGKLFDELTASYKLEKQQEQQKAQERQELWQGLEELRLRRLQGTQGAKE
  APLQRLTPQVAASGGQS
• Function: As the regulatory component of the serine/threonine-protein phosphatase 2A (PP2A) holoenzyme, modulates substrate specificity, subcellular localization, and responsiveness to phosphorylation. The phosphorylated form mediates the interaction between PP2A and AKT1, leading to AKT1 dephosphorylation.
• Tissue Specificity: Highest expression in brain.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  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)
• Reactome Pathway:
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  XBP1(S) activates chaperone genes (R-HSA-381038)
  CTLA4 inhibitory signaling (R-HSA-389513)
  Platelet sensitization by LDL (R-HSA-432142)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Signaling by GSK3beta mutants (R-HSA-5339716)
  CTNNB1 S33 mutants aren't phosphorylated (R-HSA-5358747)
  CTNNB1 S37 mutants aren't phosphorylated (R-HSA-5358749)
  CTNNB1 S45 mutants aren't phosphorylated (R-HSA-5358751)
  CTNNB1 T41 mutants aren't phosphorylated (R-HSA-5358752)
  APC truncation mutants have impaired AXIN binding (R-HSA-5467337)
  AXIN missense mutants destabilize the destruction complex (R-HSA-5467340)
  Truncations of AMER1 destabilize the destruction complex (R-HSA-5467348)
  RHO GTPases Activate Formins (R-HSA-5663220)
  RAF activation (R-HSA-5673000)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[1]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[2]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Biomarker	[4]

1 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 Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[5]

9 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 56 kDa regulatory subunit beta isoform (PPP2R5B).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit beta isoform (PPP2R5B).	[13]

References

• [1] Mutation analysis of five candidate genes in familial breast cancer.Breast Cancer Res Treat. 2007 Nov;105(3):377-89. doi: 10.1007/s10549-006-9461-z. Epub 2006 Dec 23.
• [2] PPP2R5B, a regulatory subunit of PP2A, contributes to adipocyte insulin resistance.Mol Cell Endocrinol. 2016 Dec 5;437:97-107. doi: 10.1016/j.mce.2016.08.016. Epub 2016 Aug 10.
• [3] Deletion of 11q12.3-11q13.1 in a patient with intellectual disability and childhood facial features resembling Cornelia de Lange syndrome.Gene. 2015 Nov 1;572(1):130-134. doi: 10.1016/j.gene.2015.07.016. Epub 2015 Jul 8.
• [4] Mapping of the gene encoding the B56 beta subunit of protein phosphatase 2A (PPP2R5B) to a 0.5-Mb region of chromosome 11q13 and its exclusion as a candidate gene for multiple endocrine neoplasia type 1 (MEN1).Hum Genet. 1997 Sep;100(3-4):481-5. doi: 10.1007/s004390050538.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] 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.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.