Details of Drug Off-Target (DOT)

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

• DOT Name: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2)
• Synonyms: EC 3.1.4.11; Phosphoinositide phospholipase C-beta-2; Phospholipase C-beta-2; PLC-beta-2
• Gene Name: PLCB2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Adenocarcinoma
  Breast neoplasm
  Chronic kidney disease
  Hepatocellular carcinoma
  Melanoma
  Myocardial infarction
  Neoplasm
  Advanced cancer
  Coxsackie virus infection
  Invasive breast carcinoma
  Invasive ductal breast carcinoma
  Obesity
• UniProt ID: PLCB2_HUMAN
• PDB ID: 2FJU; 2ZKM
• EC Number: 3.1.4.11
• Pfam ID: PF00168 ; PF09279 ; PF17787 ; PF00388 ; PF00387 ; PF08703
• Sequence:
  MSLLNPVLLPPKVKAYLSQGERFIKWDDETTVASPVILRVDPKGYYLYWTYQSKEMEFLD
  ITSIRDTRFGKFAKMPKSQKLRDVFNMDFPDNSFLLKTLTVVSGPDMVDLTFHNFVSYKE
  NVGKAWAEDVLALVKHPLTANASRSTFLDKILVKLKMQLNSEGKIPVKNFFQMFPADRKR
  VEAALSACHLPKGKNDAINPEDFPEPVYKSFLMSLCPRPEIDEIFTSYHAKAKPYMTKEH
  LTKFINQKQRDSRLNSLLFPPARPDQVQGLIDKYEPSGINAQRGQLSPEGMVWFLCGPEN
  SVLAQDKLLLHHDMTQPLNHYFINSSHNTYLTAGQFSGLSSAEMYRQVLLSGCRCVELDC
  WKGKPPDEEPIITHGFTMTTDIFFKEAIEAIAESAFKTSPYPIILSFENHVDSPRQQAKM
  AEYCRTIFGDMLLTEPLEKFPLKPGVPLPSPEDLRGKILIKNKKNQFSGPTSSSKDTGGE
  AEGSSPPSAPAGEGTVWAGEEGTELEEEEVEEEEEEESGNLDEEEIKKMQSDEGTAGLEV
  TAYEEMSSLVNYIQPTKFVSFEFSAQKNRSYVISSFTELKAYDLLSKASVQFVDYNKRQM
  SRIYPKGTRMDSSNYMPQMFWNAGCQMVALNFQTMDLPMQQNMAVFEFNGQSGYLLKHEF
  MRRPDKQFNPFSVDRIDVVVATTLSITVISGQFLSERSVRTYVEVELFGLPGDPKRRYRT
  KLSPSTNSINPVWKEEPFVFEKILMPELASLRVAVMEEGNKFLGHRIIPINALNSGYHHL
  CLHSESNMPLTMPALFIFLEMKDYIPGAWADLTVALANPIKFFSAHDTKSVKLKEAMGGL
  PEKPFPLASPVASQVNGALAPTSNGSPAARAGAREEAMKEAAEPRTASLEELRELKGVVK
  LQRRHEKELRELERRGARRWEELLQRGAAQLAELGPPGVGGVGACKLGPGKGSRKKRSLP
  REESAGAAPGEGPEGVDGRVRELKDRLELELLRQGEEQYECVLKRKEQHVAEQISKMMEL
  AREKQAAELKALKETSENDTKEMKKKLETKRLERIQGMTKVTTDKMAQERLKREINNSHI
  QEVVQVIKQMTENLERHQEKLEEKQAACLEQIREMEKQFQKEALAEYEARMKGLEAEVKE
  SVRACLRTCFPSEAKDKPERACECPPELCEQDPLIAKADAQESRL
• Function: The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Chemokine sig.ling pathway (hsa04062)
  Phosphatidylinositol sig.ling system (hsa04070)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Wnt sig.ling pathway (hsa04310)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Taste transduction (hsa04742)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  GnRH secretion (hsa04929)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Carbohydrate digestion and absorption (hsa04973)
  Alzheimer disease (hsa05010)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Amoebiasis (hsa05146)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  Synthesis of IP3 and IP4 in the cytosol (R-HSA-1855204)
  Acetylcholine regulates insulin secretion (R-HSA-399997)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G beta (R-HSA-418217)
  Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion (R-HSA-434316)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  PLC beta mediated events (R-HSA-112043)
• BioCyc Pathway: MetaCyc:HS06408-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Disputed	Altered Expression	[6]
Coxsackie virus infection	DISY1VPA	Limited	Altered Expression	[7]
Invasive breast carcinoma	DISANYTW	Limited	Altered Expression	[3]
Invasive ductal breast carcinoma	DIS43J58	Limited	Genetic Variation	[3]
Obesity	DIS47Y1K	Limited	Altered Expression	[8]

9 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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[17]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[19]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cytarabine	DMZD5QR	Approved	Cytarabine affects the localization of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate affects the localization of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[14]

2 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 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[15]
Paraquat	DMR8O3X	Investigative	Paraquat increases the phosphorylation of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLCB2).	[18]

References

• [1] Identification of genes and pathways associated with MDR in MCF-7/MDR breast cancer cells by RNA-seq analysis.Mol Med Rep. 2018 May;17(5):6211-6226. doi: 10.3892/mmr.2018.8704. Epub 2018 Mar 7.
• [2] Distinct Prognostic Values of Phospholipase C Beta Family Members for Non-Small Cell Lung Carcinoma.Biomed Res Int. 2019 Apr 7;2019:4256524. doi: 10.1155/2019/4256524. eCollection 2019.
• [3] Ectopic expression of PLC-2 in non-invasive breast tumor cells plays a protective role against malignant progression and is correlated with the deregulation of miR-146a.Mol Carcinog. 2019 May;58(5):708-721. doi: 10.1002/mc.22964. Epub 2019 Jan 16.
• [4] Identification of 13 novel susceptibility loci for early-onset myocardial infarction, hypertension, or chronic kidney disease.Int J Mol Med. 2018 Nov;42(5):2415-2436. doi: 10.3892/ijmm.2018.3852. Epub 2018 Sep 4.
• [5] Diagnostic and prognostic value of mRNA expression of phospholipase C family genes in hepatitis B virusassociated hepatocellular carcinoma.Oncol Rep. 2019 May;41(5):2855-2875. doi: 10.3892/or.2019.7066. Epub 2019 Mar 14.
• [6] Knockdown of PLCB2 expression reduces melanoma cell viability and promotes melanoma cell apoptosis by altering Ras/Raf/MAPK signals.Mol Med Rep. 2020 Jan;21(1):420-428. doi: 10.3892/mmr.2019.10798. Epub 2019 Nov 6.
• [7] PLC2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1.Nat Commun. 2019 Feb 14;10(1):746. doi: 10.1038/s41467-019-08524-3.
• [8] Obesity is associated with altered gene expression in human tastebuds.Int J Obes (Lond). 2019 Jul;43(7):1475-1484. doi: 10.1038/s41366-018-0303-y. Epub 2019 Jan 29.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] 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.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] Protein kinase CbetaII activation by 1-beta-D-arabinofuranosylcytosine is antagonistic to stimulation of apoptosis and Bcl-2alpha down-regulation. J Biol Chem. 1997 Sep 19;272(38):23481-4. doi: 10.1074/jbc.272.38.23481.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] 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.
• [18] Suppression of ROS generation by 4,4-diaminodiphenylsulfone in non-phagocytic human diploid fibroblasts. Exp Mol Med. 2010 Mar 31;42(3):223-32. doi: 10.3858/emm.2010.42.3.024.
• [19] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [20] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.