Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9Q86JO)

• DOT Name: Protein phosphatase 1 regulatory subunit 12C (PPP1R12C)
• Synonyms: Protein phosphatase 1 myosin-binding subunit of 85 kDa; Protein phosphatase 1 myosin-binding subunit p85
• Gene Name: PPP1R12C
• Related Disease:
  Adenocarcinoma
  Adult glioblastoma
  Breast carcinoma
  Chronic myelomonocytic leukaemia
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Glioblastoma multiforme
  Head and neck cancer
  Head and neck carcinoma
  HIV infectious disease
  Lung cancer
  Lung carcinoma
  Lymphoproliferative syndrome
  Malignant glioma
  Mood disorder
  Myopia
  Nasopharyngeal carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Plasma cell myeloma
  Pneumococcal meningitis
  Polycythemia
  Primary familial polycythemia due to EPO receptor mutation
  Rabies
  Thymus lymphoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Kidney cancer
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Advanced cancer
  Breast cancer
  Hepatitis C virus infection
  Mesothelioma
• UniProt ID: PP12C_HUMAN
• Pfam ID: PF12796 ; PF15898
• Sequence:
  MSGEDGPAAGPGAAAAAARERRREQLRQWGARAGAEPGPGERRARTVRFERAAEFLAACA
  GGDLDEARLMLRAADPGPGAELDPAAPPPARAVLDSTNADGISALHQACIDENLEVVRFL
  VEQGATVNQADNEGWTPLHVAASCGYLDIARYLLSHGANIAAVNSDGDLPLDLAESDAME
  GLLKAEIARRGVDVEAAKRAEEELLLHDTRCWLNGGAMPEARHPRTGASALHVAAAKGYI
  EVMRLLLQAGYDPELRDGDGWTPLHAAAHWGVEDACRLLAEHGGGMDSLTHAGQRPCDLA
  DEEVLSLLEELARKQEDLRNQKEASQSRGQEPQAPSSSKHRRSSVCRLSSREKISLQDLS
  KERRPGGAGGPPIQDEDEGEEGPTEPPPAEPRTLNGVSSPPHPSPKSPVQLEEAPFSRRF
  GLLKTGSSGALGPPERRTAEGAPGAGLQRSASSSWLEGTSTQAKELRLARITPTPSPKLP
  EPSVLSEVTKPPPCLENSSPPSRIPEPESPAKPNVPTASTAPPADSRDRRRSYQMPVRDE
  ESESQRKARSRLMRQSRRSTQGVTLTDLKEAEKAAGKAPESEKPAQSLDPSRRPRVPGVE
  NSDSPAQRAEAPDGQGPGPQAAREHRKVGKEWRGPAEGEEAEPADRSQESSTLEGGPSAR
  RQRWQRDLNPEPEPESEEPDGGFRTLYAELRRENERLREALTETTLRLAQLKVELERATQ
  RQERFAERPALLELERFERRALERKAAELEEELKALSDLRADNQRLKDENAALIRVISKL
  SK
• Function: Regulates myosin phosphatase activity.
• Tissue Specificity: Ubiquitously expressed. Highly expressed in heart.
• KEGG Pathway:
  Vascular smooth muscle contraction (hsa04270)
  Focal adhesion (hsa04510)
  Regulation of actin cytoskeleton (hsa04810)
  Oxytocin sig.ling pathway (hsa04921)
  Proteoglycans in cancer (hsa05205)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Genetic Variation	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[7]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[7]
HIV infectious disease	DISO97HC	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Lymphoproliferative syndrome	DISMVL8O	Strong	Biomarker	[5]
Malignant glioma	DISFXKOV	Strong	Biomarker	[9]
Mood disorder	DISLVMWO	Strong	Biomarker	[10]
Myopia	DISK5S60	Strong	Genetic Variation	[11]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[14]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[15]
Pneumococcal meningitis	DISM5U0L	Strong	Biomarker	[16]
Polycythemia	DIS8B6VW	Strong	Genetic Variation	[17]
Primary familial polycythemia due to EPO receptor mutation	DISFVI97	Strong	Biomarker	[17]
Rabies	DISSC4V5	Strong	Biomarker	[16]
Thymus lymphoma	DISJ17C5	Strong	Biomarker	[5]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[18]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[19]
Kidney cancer	DISBIPKM	moderate	Altered Expression	[18]
Prostate cancer	DISF190Y	moderate	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[20]
Renal carcinoma	DISER9XT	moderate	Altered Expression	[18]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[18]
Small lymphocytic lymphoma	DIS30POX	moderate	Genetic Variation	[21]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[22]
Breast cancer	DIS7DPX1	Limited	Biomarker	[3]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[23]
Mesothelioma	DISKWK9M	Limited	Altered Expression	[24]

5 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 Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Protein phosphatase 1 regulatory subunit 12C (PPP1R12C).	[30]

References

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• [2] Yes and PI3K bind CD95 to signal invasion of glioblastoma.Cancer Cell. 2008 Mar;13(3):235-48. doi: 10.1016/j.ccr.2008.02.003.
• [3] Hyaluronic acid decorated pluronic P85 solid lipid nanoparticles as a potential carrier to overcome multidrug resistance in cervical and breast cancer.Biomed Pharmacother. 2017 Feb;86:595-604. doi: 10.1016/j.biopha.2016.12.041. Epub 2016 Dec 24.
• [4] Juvenile myelomonocytic leukaemia-associated mutation in Cbl promotes resistance to apoptosis via the Lyn-PI3K/AKT pathway.Oncogene. 2015 Feb 5;34(6):789-97. doi: 10.1038/onc.2013.596. Epub 2014 Jan 27.
• [5] Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO).Leukemia. 2002 May;16(5):894-901. doi: 10.1038/sj.leu.2402484.
• [6] Inhibition of Growth and Metastasis of Colon Cancer by Delivering 5-Fluorouracil-loaded Pluronic P85 Copolymer Micelles.Sci Rep. 2016 Feb 11;6:20896. doi: 10.1038/srep20896.
• [7] Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer.Oral Oncol. 2018 Mar;78:56-63. doi: 10.1016/j.oraloncology.2018.01.014. Epub 2018 Feb 20.
• [8] Tim-3 is a Marker of Plasmacytoid Dendritic Cell Dysfunction during HIV Infection and Is Associated with the Recruitment of IRF7 and p85 into Lysosomes and with the Submembrane Displacement of TLR9.J Immunol. 2017 Apr 15;198(8):3181-3194. doi: 10.4049/jimmunol.1601298. Epub 2017 Mar 6.
• [9] Loss of merlin-p85 protein complex in NF2-related tumors.Int J Oncol. 1998 May;12(5):1073-8. doi: 10.3892/ijo.12.5.1073.
• [10] Abnormal G protein alpha(s) - and alpha(i2)-subunit mRNA expression in bipolar affective disorder.Mol Psychiatry. 1998 Nov;3(6):512-20. doi: 10.1038/sj.mp.4000393.
• [11] Adenomatous Polyposis Coli Mutation Leads to Myopia Development in Mice.PLoS One. 2015 Oct 23;10(10):e0141144. doi: 10.1371/journal.pone.0141144. eCollection 2015.
• [12] LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85.Cancer Lett. 2018 Apr 28;420:38-48. doi: 10.1016/j.canlet.2018.01.067. Epub 2018 Jan 31.
• [13] The p85 isoform of the kinase S6K1 functions as a secreted oncoprotein to facilitate cell migration and tumor growth.Sci Signal. 2018 Mar 27;11(523):eaao1052. doi: 10.1126/scisignal.aao1052.
• [14] MiR-503 targets PI3K p85 and IKK- and suppresses progression of non-small cell lung cancer.Int J Cancer. 2014 Oct 1;135(7):1531-42. doi: 10.1002/ijc.28799. Epub 2014 Mar 27.
• [15] A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells.Hum Mol Genet. 2009 Jun 1;18(11):1951-61. doi: 10.1093/hmg/ddp116. Epub 2009 Mar 13.
• [16] Brain-targeted delivery of PEGylated nano-bacitracin A against Penicillin-sensitive and -resistant Pneumococcal meningitis: formulated with RVG(29) and Pluronic() P85 unimers.Drug Deliv. 2018 Nov;25(1):1886-1897. doi: 10.1080/10717544.2018.1486473.
• [17] Ligand-induced EpoR internalization is mediated by JAK2 and p85 and is impaired by mutations responsible for primary familial and congenital polycythemia.Blood. 2009 May 21;113(21):5287-97. doi: 10.1182/blood-2008-09-179572. Epub 2009 Mar 31.
• [18] Anticancer activity of Schiff base-Poloxamer P85 combination against kidney cancer.Int Urol Nephrol. 2018 Feb;50(2):247-255. doi: 10.1007/s11255-017-1782-9. Epub 2017 Dec 29.
• [19] DC-SIGN-LEF1/TCF1-miR-185 feedback loop promotes colorectal cancer invasion and metastasis.Cell Death Differ. 2020 Jan;27(1):379-395. doi: 10.1038/s41418-019-0361-2. Epub 2019 Jun 19.
• [20] LSD1 Activates PI3K/AKT Signaling Through Regulating p85 Expression in Prostate Cancer Cells.Front Oncol. 2019 Aug 2;9:721. doi: 10.3389/fonc.2019.00721. eCollection 2019.
• [21] Integrative genomic analysis implicates gain of PIK3CA at 3q26 and MYC at 8q24 in chronic lymphocytic leukemia.Clin Cancer Res. 2012 Jul 15;18(14):3791-802. doi: 10.1158/1078-0432.CCR-11-2342. Epub 2012 May 23.
• [22] Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases.Front Immunol. 2018 Mar 19;9:575. doi: 10.3389/fimmu.2018.00575. eCollection 2018.
• [23] Hepatitis C virus NS5A protein interacts with beta-catenin and stimulates its transcriptional activity in a phosphoinositide-3 kinase-dependent fashion.J Gen Virol. 2010 Feb;91(Pt 2):373-81. doi: 10.1099/vir.0.015305-0. Epub 2009 Oct 21.
• [24] Reduced cell viability and apoptosis induction in human thyroid carcinoma and mesothelioma cells exposed to cidofovir.Toxicol In Vitro. 2017 Jun;41:49-55. doi: 10.1016/j.tiv.2017.02.008. Epub 2017 Feb 20.
• [25] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [26] 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.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [29] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [30] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.