Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRL8QP8)

• DOT Name: Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4)
• Synonyms: PI3-kinase regulatory subunit 4; EC 2.7.11.1; PI3-kinase p150 subunit; Phosphoinositide 3-kinase adaptor protein
• Gene Name: PIK3R4
• Related Disease:
  Multiple sclerosis
  Amyotrophic lateral sclerosis
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Cervical carcinoma
  Ciliopathy
  Dyschromatosis symmetrica hereditaria
  Epilepsy
  Episodic kinesigenic dyskinesia 1
  Epithelial ovarian cancer
  Frontotemporal dementia
  Gastric cancer
  Metastatic malignant neoplasm
  Neoplasm
  Ovarian cancer
  rubella
  Stomach cancer
  Warburg micro syndrome 1
  Advanced cancer
  Chediak-Higashi syndrome
  Danon disease
  Glycogen storage disease type II
  Lysosomal storage disease
  Myopathy
  Parkinsonian disorder
  Type-1/2 diabetes
• UniProt ID: PI3R4_HUMAN
• PDB ID: 7BL1; 8SOR; 8SRQ
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00400
• Sequence:
  MGNQLAGIAPSQILSVESYFSDIHDFEYDKSLGSTRFFKVARAKHREGLVVVKVFAIQDP
  TLPLTSYKQELEELKIRLNSAQNCLPFQKASEKASEKAAMLFRQYVRDNLYDRISTRPFL
  NNIEKRWIAFQILTAVDQAHKSGVRHGDIKTENVMVTSWNWVLLTDFASFKPTYLPEDNP
  ADFNYFFDTSRRRTCYIAPERFVDGGMFATELEYMRDPSTPLVDLNSNQRTRGELKRAMD
  IFSAGCVIAELFTEGVPLFDLSQLLAYRNGHFFPEQVLNKIEDHSIRELVTQMIHREPDK
  RLEAEDYLKQQRGNAFPEIFYTFLQPYMAQFAKETFLSADERILVIRKDLGNIIHNLCGH
  DLPEKAEGEPKENGLVILVSVITSCLQTLKYCDSKLAALELILHLAPRLSVEILLDRITP
  YLLHFSNDSVPRVRAEALRTLTKVLALVKEVPRNDINIYPEYILPGIAHLAQDDATIVRL
  AYAENIALLAETALRFLELVQLKNLNMENDPNNEEIDEVTHPNGNYDTELQALHEMVQQK
  VVTLLSDPENIVKQTLMENGITRLCVFFGRQKANDVLLSHMITFLNDKNDWHLRGAFFDS
  IVGVAAYVGWQSSSILKPLLQQGLSDAEEFVIVKALYALTCMCQLGLLQKPHVYEFASDI
  APFLCHPNLWIRYGAVGFITVVARQISTADVYCKLMPYLDPYITQPIIQIERKLVLLSVL
  KEPVSRSIFDYALRSKDITSLFRHLHMRQKKRNGSLPDCPPPEDPAIAQLLKKLLSQGMT
  EEEEDKLLALKDFMMKSNKAKANIVDQSHLHDSSQKGVIDLAALGITGRQVDLVKTKQEP
  DDKRARKHVKQDSNVNEEWKSMFGSLDPPNMPQALPKGSDQEVIQTGKPPRSESSAGICV
  PLSTSSQVPEVTTVQNKKPVIPVLSSTILPSTYQIRITTCKTELQQLIQQKREQCNAERI
  AKQMMENAEWESKPPPPGWRPKGLLVAHLHEHKSAVNRIRVSDEHSLFATCSNDGTVKIW
  NSQKMEGKTTTTRSILTYSRIGGRVKTLTFCQGSHYLAIASDNGAVQLLGIEASKLPKSP
  KIHPLQSRILDQKEDGCVVDMHHFNSGAQSVLAYATVNGSLVGWDLRSSSNAWTLKHDLK
  SGLITSFAVDIHQCWLCIGTSSGTMACWDMRFQLPISSHCHPSRARIRRLSMHPLYQSWV
  IAAVQGNNEVSMWDMETGDRRFTLWASSAPPLSELQPSPHSVHGIYCSPADGNPILLTAG
  SDMKIRFWDLAYPERSYVVAGSTSSPSVSYYRKIIEGTEVVQEIQNKQKVGPSDDTPRRG
  PESLPVGHHDIITDVATFQTTQGFIVTASRDGIVKVWK
• Function: Regulatory subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and cytokinesis, probably in the context of PI3KC3-C2.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
  Apelin sig.ling pathway (hsa04371)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Shigellosis (hsa05131)
• Reactome Pathway:
  Macroautophagy (R-HSA-1632852)
  Synthesis of PIPs at the Golgi membrane (R-HSA-1660514)
  Synthesis of PIPs at the early endosome membrane (R-HSA-1660516)
  Synthesis of PIPs at the late endosome membrane (R-HSA-1660517)
  Toll Like Receptor 9 (TLR9) Cascade (R-HSA-168138)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9679504)
  Translation of Replicase and Assembly of the Replication Transcription Complex (R-HSA-9694676)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  PI3K Cascade (R-HSA-109704)
• BioCyc Pathway: MetaCyc:HS03788-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[1]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Dyschromatosis symmetrica hereditaria	DIS9HI9T	Strong	Biomarker	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Posttranslational Modification	[8]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Ovarian cancer	DISZJHAP	Strong	Posttranslational Modification	[8]
rubella	DISXUI9P	Strong	Biomarker	[9]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Warburg micro syndrome 1	DIS90EI2	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Chediak-Higashi syndrome	DISPJLLO	Disputed	Biomarker	[12]
Danon disease	DIS45YLU	Limited	Biomarker	[13]
Glycogen storage disease type II	DISXZPBC	Limited	Biomarker	[13]
Lysosomal storage disease	DIS6QM6U	Limited	Biomarker	[14]
Myopathy	DISOWG27	Limited	Biomarker	[14]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[15]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[20]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4).	[23]

References

• [1] The p150 subunit of dynactin (DCTN1) gene in multiple sclerosis.Acta Neurol Scand. 2007 Oct;116(4):231-4. doi: 10.1111/j.1600-0404.2007.00884.x.
• [2] ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1041-6. doi: 10.1073/pnas.1213021110. Epub 2012 Dec 28.
• [3] p150 overexpression in gastric carcinoma: the association with p53, apoptosis and cell proliferation.Int J Cancer. 2004 Nov 10;112(3):393-8. doi: 10.1002/ijc.20443.
• [4] A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi.Nat Commun. 2016 Nov 24;7:13586. doi: 10.1038/ncomms13586.
• [5] The adenosine deaminase acting on RNA 1 p150 isoform is involved in the pathogenesis of dyschromatosis symmetrica hereditaria.Br J Dermatol. 2013 Sep;169(3):637-44. doi: 10.1111/bjd.12401.
• [6] Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.Nat Neurosci. 2018 Feb;21(2):207-217. doi: 10.1038/s41593-017-0053-5. Epub 2018 Jan 8.
• [7] Vps15 is critical to mediate autophagy in AngII treated HUVECs probably by PDK1/PKC signaling pathway.Life Sci. 2019 Sep 15;233:116701. doi: 10.1016/j.lfs.2019.116701. Epub 2019 Jul 26.
• [8] Promoter methylation of the SALL2 tumor suppressor gene in ovarian cancers.Mol Oncol. 2013 Jun;7(3):419-27. doi: 10.1016/j.molonc.2012.11.005. Epub 2012 Dec 12.
• [9] Characterization of rubella-specific humoral immunity following two doses of MMR vaccine using proteome microarray technology.PLoS One. 2017 Nov 16;12(11):e0188149. doi: 10.1371/journal.pone.0188149. eCollection 2017.
• [10] Analysis on the emerging role of Rab3 GTPase-activating protein in Warburg Micro and Martsolf syndrome.Methods Enzymol. 2008;438:131-9. doi: 10.1016/S0076-6879(07)38009-9.
• [11] Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer.Biochem Biophys Res Commun. 2014 Jun 27;449(2):208-15. doi: 10.1016/j.bbrc.2014.05.006. Epub 2014 May 15.
• [12] Identification and mutation analysis of the complete gene for Chediak-Higashi syndrome.Nat Genet. 1996 Nov;14(3):307-11. doi: 10.1038/ng1196-307.
• [13] Autophagy dysregulation in Danon disease.Cell Death Dis. 2017 Jan 19;8(1):e2565. doi: 10.1038/cddis.2016.475.
• [14] Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease.EMBO Mol Med. 2013 Jun;5(6):870-90. doi: 10.1002/emmm.201202057. Epub 2013 Apr 30.
• [15] The dynactin p150 subunit: cell biology studies of sequence changes found in ALS/MND and Parkinsonian syndromes.J Neural Transm (Vienna). 2013 May;120(5):785-98. doi: 10.1007/s00702-012-0910-z. Epub 2012 Nov 11.
• [16] Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling.Nat Commun. 2015 Sep 21;6:8283. doi: 10.1038/ncomms9283.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] 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.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [22] 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.
• [23] 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.