Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZJFX5C)

• DOT Name: Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B)
• Synonyms: Ankyrin repeat domain-containing protein 4; CAAX box protein TIMAP; TGF-beta-inhibited membrane-associated protein; hTIMAP
• Gene Name: PPP1R16B
• Related Disease:
  Plasma cell myeloma
  Schizophrenia
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Alcoholic cirrhosis of liver
  Rectal carcinoma
• UniProt ID: PP16B_HUMAN
• Pfam ID: PF12796
• Sequence:
  MASHVDLLTELQLLEKVPTLERLRAAQKRRAQQLKKWAQYEQDLQHRKRKHERKRSTGGR
  RKKVSFEASVALLEASLRNDAEEVRYFLKNKVSPDLCNEDGLTALHQCCIDNFEEIVKLL
  LSHGANVNAKDNELWTPLHAAATCGHINLVKILVQYGADLLAVNSDGNMPYDLCEDEPTL
  DVIETCMAYQGITQEKINEMRVAPEQQMIADIHCMIAAGQDLDWIDAQGATLLHIAGANG
  YLRAAELLLDHGVRVDVKDWDGWEPLHAAAFWGQMQMAELLVSHGASLSARTSMDEMPID
  LCEEEEFKVLLLELKHKHDVIMKSQLRHKSSLSRRTSSAGSRGKVVRRASLSDRTNLYRK
  EYEGEAILWQRSAAEDQRTSTYNGDIRETRTDQENKDPNPRLEKPVLLSEFPTKIPRGEL
  DMPVENGLRAPVSAYQYALANGDVWKVHEVPDYSMAYGNPGVADATPPWSSYKEQSPQTL
  LELKRQRAAAKLLSHPFLSTHLGSSMARTGESSSEGKAPLIGGRTSPYSSNGTSVYYTVT
  SGDPPLLKFKAPIEEMEEKVHGCCRIS
• Function: Regulator of protein phosphatase 1 (PP1) that acts as a positive regulator of pulmonary endothelial cell (EC) barrier function. Involved in the regulation of the PI3K/AKT signaling pathway, angiogenesis and endothelial cell proliferation. Regulates angiogenesis and endothelial cell proliferation through the control of ECE1 dephosphorylation, trafficking and activity. Protects the endothelial barrier from lipopolysaccharide (LPS)-induced vascular leakage. Involved in the regulation of endothelial cell filopodia extension. May be a downstream target for TGF-beta1 signaling cascade in endothelial cells. Involved in PKA-mediated moesin dephosphorylation which is important in EC barrier protection against thrombin stimulation. Promotes the interaction of PPP1CA with RPSA/LAMR1 and in turn facilitates the dephosphorylation of RPSA/LAMR1. Involved in the dephosphorylation of EEF1A1.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[2]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[3]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[3]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[3]
Alcoholic cirrhosis of liver	DISQ1WRT	moderate	Genetic Variation	[3]
Rectal carcinoma	DIS8FRR7	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B) decreases the response to substance of Camptothecin.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[10]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[12]

2 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 phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein phosphatase 1 regulatory inhibitor subunit 16B (PPP1R16B).	[11]

References

• [1] Ectopic expression of MAFB gene in human myeloma cells carrying (14;20)(q32;q11) chromosomal translocations.Jpn J Cancer Res. 2001 Jun;92(6):638-44. doi: 10.1111/j.1349-7006.2001.tb01142.x.
• [2] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [3] Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis.Genes (Basel). 2017 Jul 17;8(7):183. doi: 10.3390/genes8070183.
• [4] Affinity proteomics led identification of vimentin as a potential biomarker in colon cancers: insights from serological screening and computational modelling.Mol Biosyst. 2015 Jan;11(1):159-69. doi: 10.1039/c4mb00506f. Epub 2014 Oct 16.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [9] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [10] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [11] 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.
• [12] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [13] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.