Details of Drug Off-Target (DOT)

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

• DOT Name: Agrin (AGRN)
• Gene Name: AGRN
• Related Disease:
  Thyroid gland papillary carcinoma
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Congenital myasthenic syndrome
  Congenital myasthenic syndrome 8
  Fetal akinesia deformation sequence 1
  Lung adenocarcinoma
  Obsolete presynaptic congenital myasthenic syndrome
  Postsynaptic congenital myasthenic syndrome
• UniProt ID: AGRIN_HUMAN
• PDB ID: 8S9P
• Pfam ID: PF00008 ; PF00050 ; PF07648 ; PF00053 ; PF00054 ; PF03146 ; PF01390
• Sequence:
  MAGRSHPGPLRPLLPLLVVAACVLPGAGGTCPERALERREEEANVVLTGTVEEILNVDPV
  QHTYSCKVRVWRYLKGKDLVARESLLDGGNKVVISGFGDPLICDNQVSTGDTRIFFVNPA
  PPYLWPAHKNELMLNSSLMRITLRNLEEVEFCVEDKPGTHFTPVPPTPPDACRGMLCGFG
  AVCEPNAEGPGRASCVCKKSPCPSVVAPVCGSDASTYSNECELQRAQCSQQRRIRLLSRG
  PCGSRDPCSNVTCSFGSTCARSADGLTASCLCPATCRGAPEGTVCGSDGADYPGECQLLR
  RACARQENVFKKFDGPCDPCQGALPDPSRSCRVNPRTRRPEMLLRPESCPARQAPVCGDD
  GVTYENDCVMGRSGAARGLLLQKVRSGQCQGRDQCPEPCRFNAVCLSRRGRPRCSCDRVT
  CDGAYRPVCAQDGRTYDSDCWRQQAECRQQRAIPSKHQGPCDQAPSPCLGVQCAFGATCA
  VKNGQAACECLQACSSLYDPVCGSDGVTYGSACELEATACTLGREIQVARKGPCDRCGQC
  RFGALCEAETGRCVCPSECVALAQPVCGSDGHTYPSECMLHVHACTHQISLHVASAGPCE
  TCGDAVCAFGAVCSAGQCVCPRCEHPPPGPVCGSDGVTYGSACELREAACLQQTQIEEAR
  AGPCEQAECGSGGSGSGEDGDCEQELCRQRGGIWDEDSEDGPCVCDFSCQSVPGSPVCGS
  DGVTYSTECELKKARCESQRGLYVAAQGACRGPTFAPLPPVAPLHCAQTPYGCCQDNITA
  ARGVGLAGCPSACQCNPHGSYGGTCDPATGQCSCRPGVGGLRCDRCEPGFWNFRGIVTDG
  RSGCTPCSCDPQGAVRDDCEQMTGLCSCKPGVAGPKCGQCPDGRALGPAGCEADASAPAT
  CAEMRCEFGARCVEESGSAHCVCPMLTCPEANATKVCGSDGVTYGNECQLKTIACRQGLQ
  ISIQSLGPCQEAVAPSTHPTSASVTVTTPGLLLSQALPAPPGALPLAPSSTAHSQTTPPP
  SSRPRTTASVPRTTVWPVLTVPPTAPSPAPSLVASAFGESGSTDGSSDEELSGDQEASGG
  GSGGLEPLEGSSVATPGPPVERASCYNSALGCCSDGKTPSLDAEGSNCPATKVFQGVLEL
  EGVEGQELFYTPEMADPKSELFGETARSIESTLDDLFRNSDVKKDFRSVRLRDLGPGKSV
  RAIVDVHFDPTTAFRAPDVARALLRQIQVSRRRSLGVRRPLQEHVRFMDFDWFPAFITGA
  TSGAIAAGATARATTASRLPSSAVTPRAPHPSHTSQPVAKTTAAPTTRRPPTTAPSRVPG
  RRPPAPQQPPKPCDSQPCFHGGTCQDWALGGGFTCSCPAGRGGAVCEKVLGAPVPAFEGR
  SFLAFPTLRAYHTLRLALEFRALEPQGLLLYNGNARGKDFLALALLDGRVQLRFDTGSGP
  AVLTSAVPVEPGQWHRLELSRHWRRGTLSVDGETPVLGESPSGTDGLNLDTDLFVGGVPE
  DQAAVALERTFVGAGLRGCIRLLDVNNQRLELGIGPGAATRGSGVGECGDHPCLPNPCHG
  GAPCQNLEAGRFHCQCPPGRVGPTCADEKSPCQPNPCHGAAPCRVLPEGGAQCECPLGRE
  GTFCQTASGQDGSGPFLADFNGFSHLELRGLHTFARDLGEKMALEVVFLARGPSGLLLYN
  GQKTDGKGDFVSLALRDRRLEFRYDLGKGAAVIRSREPVTLGAWTRVSLERNGRKGALRV
  GDGPRVLGESPKSRKVPHTVLNLKEPLYVGGAPDFSKLARAAAVSSGFDGAIQLVSLGGR
  QLLTPEHVLRQVDVTSFAGHPCTRASGHPCLNGASCVPREAAYVCLCPGGFSGPHCEKGL
  VEKSAGDVDTLAFDGRTFVEYLNAVTESELANEIPVPETLDSGALHSEKALQSNHFELSL
  RTEATQGLVLWSGKATERADYVALAIVDGHLQLSYNLGSQPVVLRSTVPVNTNRWLRVVA
  HREQREGSLQVGNEAPVTGSSPLGATQLDTDGALWLGGLPELPVGPALPKAYGTGFVGCL
  RDVVVGRHPLHLLEDAVTKPELRPCPTP
• Function: [Isoform 1]: Heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.; [Isoform 2]: Transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases.; Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.; Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation.; [Agrin N-terminal 110 kDa subunit]: Is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling; [Agrin C-terminal 22 kDa fragment]: This released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia.
• Tissue Specificity: Expressed in basement membranes of lung and kidney. Muscle- and neuron-specific isoforms are found. Isoforms (y+) with the 4 AA insert and (z+8) isoforms with the 8 AA insert are all neuron-specific. Isoforms (z+11) are found in both neuronal and non-neuronal tissues.
• KEGG Pathway:
  ECM-receptor interaction (hsa04512)
  Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway:
  HS-GAG biosynthesis (R-HSA-2022928)
  HS-GAG degradation (R-HSA-2024096)
  Integrin cell surface interactions (R-HSA-216083)
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  ECM proteoglycans (R-HSA-3000178)
  Defective B4GALT7 causes EDS, progeroid type (R-HSA-3560783)
  Defective B3GAT3 causes JDSSDHD (R-HSA-3560801)
  Defective EXT2 causes exostoses 2 (R-HSA-3656237)
  Defective EXT1 causes exostoses 1, TRPS2 and CHDS (R-HSA-3656253)
  NCAM1 interactions (R-HSA-419037)
  Defective B3GALT6 causes EDSP2 and SEMDJL1 (R-HSA-4420332)
  Attachment and Entry (R-HSA-9694614)
  Retinoid metabolism and transport (R-HSA-975634)
  A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Congenital myasthenic syndrome	DISJLG2T	Strong	Genetic Variation	[5]
Congenital myasthenic syndrome 8	DISICPPN	Strong	Autosomal recessive	[6]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Obsolete presynaptic congenital myasthenic syndrome	DISCATK3	Supportive	Autosomal dominant	[8]
Postsynaptic congenital myasthenic syndrome	DIS92VN2	Supportive	Autosomal recessive	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Agrin (AGRN).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Agrin (AGRN).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Agrin (AGRN).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Agrin (AGRN).	[21]

20 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 Agrin (AGRN).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Agrin (AGRN).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Agrin (AGRN).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Agrin (AGRN).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Agrin (AGRN).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Agrin (AGRN).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Agrin (AGRN).	[16]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Agrin (AGRN).	[17]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Agrin (AGRN).	[18]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Agrin (AGRN).	[10]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Agrin (AGRN).	[10]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Agrin (AGRN).	[10]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Agrin (AGRN).	[18]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Agrin (AGRN).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Agrin (AGRN).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Agrin (AGRN).	[20]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Agrin (AGRN).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Agrin (AGRN).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Agrin (AGRN).	[23]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Agrin (AGRN).	[24]

References

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• [3] Oncogenic Properties of NEAT1 in Prostate Cancer Cells Depend on the CDC5L-AGRN Transcriptional Regulation Circuit.Cancer Res. 2018 Aug 1;78(15):4138-4149. doi: 10.1158/0008-5472.CAN-18-0688. Epub 2018 Jun 5.
• [4] Amyloid beta induces cellular relocalization and production of agrin and glypican-1.Brain Res. 2009 Mar 13;1260:38-46. doi: 10.1016/j.brainres.2008.12.063. Epub 2009 Jan 7.
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• [8] LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. Hum Genet. 2012 Jul;131(7):1123-35. doi: 10.1007/s00439-011-1132-4. Epub 2011 Dec 29.
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• [11] 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.
• [12] 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.
• [13] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [17] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [18] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [24] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.