Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR1STMJ)

• DOT Name: Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C)
• Synonyms: PP6C; EC 3.1.3.16
• Gene Name: PPP6C
• Related Disease:
  Advanced cancer
  Coeliac disease
  Cutaneous melanoma
  Hepatocellular carcinoma
  Lung squamous cell carcinoma
  Malignant mesothelioma
  Melanoma
  Psoriasis
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  High blood pressure
  Metastatic melanoma
• UniProt ID: PPP6_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MAPLDLDKYVEIARLCKYLPENDLKRLCDYVCDLLLEESNVQPVSTPVTVCGDIHGQFYD
  LCELFRTGGQVPDTNYIFMGDFVDRGYYSLETFTYLLALKAKWPDRITLLRGNHESRQIT
  QVYGFYDECQTKYGNANAWRYCTKVFDMLTVAALIDEQILCVHGGLSPDIKTLDQIRTIE
  RNQEIPHKGAFCDLVWSDPEDVDTWAISPRGAGWLFGAKVTNEFVHINNLKLICRAHQLV
  HEGYKFMFDEKLVTVWSAPNYCYRCGNIASIMVFKDVNTREPKLFRAVPDSERVIPPRTT
  TPYFL
• Function: Catalytic subunit of protein phosphatase 6 (PP6). PP6 is a component of a signaling pathway regulating cell cycle progression in response to IL2 receptor stimulation. N-terminal domain restricts G1 to S phase progression in cancer cells, in part through control of cyclin D1. During mitosis, regulates spindle positioning. Down-regulates MAP3K7 kinase activation of the IL1 signaling pathway by dephosphorylation of MAP3K7. Participates also in the innate immune defense against viruses by desphosphorylating RIGI, an essential step that triggers RIGI-mediated signaling activation. Also regulates innate immunity by acting as a negative regulator of the cGAS-STING pathway: mediates dephosphorylation and inactivation of CGAS and STING1. CGAS dephosphorylation at 'Ser-435' impairs its ability to bind GTP, thereby inactivating it.
• Tissue Specificity: Ubiquitously expressed in all tissues tested with highest expression levels in testis, heart, kidney, brain, stomach, liver and skeletal muscle and lowest in placenta, lung colon and spleen.
• Reactome Pathway:
  COPII-mediated vesicle transport (R-HSA-204005)
  Telomere Extension By Telomerase (R-HSA-171319)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[2]
Cutaneous melanoma	DIS3MMH9	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[3]
Malignant mesothelioma	DISTHJGH	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[6]
Psoriasis	DIS59VMN	Strong	Biomarker	[7]
Thyroid cancer	DIS3VLDH	moderate	Biomarker	[8]
Thyroid gland carcinoma	DISMNGZ0	moderate	Biomarker	[8]
Thyroid tumor	DISLVKMD	moderate	Biomarker	[8]
High blood pressure	DISY2OHH	Limited	Biomarker	[9]
Metastatic melanoma	DISSL43L	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C).	[15]

References

• [1] Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma.Nat Genet. 2012 Sep;44(9):1006-14. doi: 10.1038/ng.2359. Epub 2012 Jul 29.
• [2] Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample.Genes Immun. 2009 Oct;10(7):659-61. doi: 10.1038/gene.2009.54. Epub 2009 Jul 23.
• [3] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [4] MicroRNA-373, a new regulator of protein phosphatase 6, functions as an oncogene in hepatocellular carcinoma.FEBS J. 2011 Jun;278(12):2044-54. doi: 10.1111/j.1742-4658.2011.08120.x. Epub 2011 May 17.
• [5] Pro-tumorigenic effects of miR-31 loss in mesothelioma.J Biol Chem. 2010 Jul 23;285(30):22809-17. doi: 10.1074/jbc.M110.100354. Epub 2010 May 12.
• [6] Phosphorylation of eIF2 triggered by mTORC1 inhibition and PP6C activation is required for autophagy and is aberrant in PP6C-mutated melanoma.Sci Signal. 2015 Mar 10;8(367):ra27. doi: 10.1126/scisignal.aaa0899.
• [7] NF-B-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis.Nat Commun. 2015 Jul 3;6:7652. doi: 10.1038/ncomms8652.
• [8] Identification of thyroid carcinoma related genes with mRMR and shortest path approaches.PLoS One. 2014 Apr 9;9(4):e94022. doi: 10.1371/journal.pone.0094022. eCollection 2014.
• [9] MicroRNA-31 Regulates Immunosuppression in Ang II (Angiotensin II)-induced Hypertension by Targeting Ppp6C (Protein Phosphatase 6c).Hypertension. 2019 May;73(5):e14-e24. doi: 10.1161/HYPERTENSIONAHA.118.12319.
• [10] PP6C hotspot mutations in melanoma display sensitivity to Aurora kinase inhibition.Mol Cancer Res. 2014 Mar;12(3):433-9. doi: 10.1158/1541-7786.MCR-13-0422. Epub 2013 Dec 12.
• [11] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.