Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLRHXP1)

• DOT Name: Synaptojanin-2 (SYNJ2)
• Synonyms: EC 3.1.3.36; Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 2
• Gene Name: SYNJ2
• Related Disease:
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cleft lip/palate
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Hairy cell leukaemia
  Joubert syndrome
  Lung carcinoma
  Muscular dystrophy
  Prostate neoplasm
  Endometriosis
  Amyotrophic lateral sclerosis
• UniProt ID: SYNJ2_HUMAN
• PDB ID: 1UFW
• EC Number: 3.1.3.36
• Pfam ID: PF08952 ; PF02383
• Sequence:
  MALSKGLRLLGRLGAEGDCSVLLEARGRDDCLLFEAGTVATLAPEEKEVIKGQYGKLTDA
  YGCLGELRLKSGGTSLSFLVLVTGCTSVGRIPDAEIYKITATDFYPLQEEAKEEERLIAL
  KKILSSGVFYFSWPNDGSRFDLTVRTQKQGDDSSEWGNSFFWNQLLHVPLRQHQVSCCDW
  LLKIICGVVTIRTVYASHKQAKACLVSRVSCERTGTRFHTRGVNDDGHVSNFVETEQMIY
  MDDGVSSFVQIRGSVPLFWEQPGLQVGSHHLRLHRGLEANAPAFDRHMVLLKEQYGQQVV
  VNLLGSRGGEEVLNRAFKKLLWASCHAGDTPMINFDFHQFAKGGKLEKLETLLRPQLKLH
  WEDFDVFTKGENVSPRFQKGTLRMNCLDCLDRTNTVQSFIALEVLHLQLKTLGLSSKPIV
  DRFVESFKAMWSLNGHSLSKVFTGSRALEGKAKVGKLKDGARSMSRTIQSNFFDGVKQEA
  IKLLLVGDVYGEEVADKGGMLLDSTALLVTPRILKAMTERQSEFTNFKRIRIAMGTWNVN
  GGKQFRSNVLRTAELTDWLLDSPQLSGATDSQDDSSPADIFAVGFEEMVELSAGNIVNAS
  TTNKKMWGEQLQKAISRSHRYILLTSAQLVGVCLYIFVRPYHVPFIRDVAIDTVKTGMGG
  KAGNKGAVGIRFQFHSTSFCFICSHLTAGQSQVKERNEDYKEITQKLCFPMGRNVFSHDY
  VFWCGDFNYRIDLTYEEVFYFVKRQDWKKLLEFDQLQLQKSSGKIFKDFHEGAINFGPTY
  KYDVGSAAYDTSDKCRTPAWTDRVLWWRKKHPFDKTAGELNLLDSDLDVDTKVRHTWSPG
  ALQYYGRAELQASDHRPVLAIVEVEVQEVDVGARERVFQEVSSFQGPLDATVVVNLQSPT
  LEEKNEFPEDLRTELMQTLGSYGTIVLVRINQGQMLVTFADSHSALSVLDVDGMKVKGRA
  VKIRPKTKDWLKGLREEIIRKRDSMAPVSPTANSCLLEENFDFTSLDYESEGDILEDDED
  YLVDEFNQPGVSDSELGGDDLSDVPGPTALAPPSKSPALTKKKQHPTYKDDADLVELKRE
  LEAVGEFRHRSPSRSLSVPNRPRPPQPPQRPPPPTGLMVKKSASDASISSGTHGQYSILQ
  TARLLPGAPQQPPKARTGISKPYNVKQIKTTNAQEAEAAIRCLLEARGGASEEALSAVAP
  RDLEASSEPEPTPGAAKPETPQAPPLLPRRPPPRVPAIKKPTLRRTGKPLSPEEQFEQQT
  VHFTIGPPETSVEAPPVVTAPRVPPVPKPRTFQPGKAAERPSHRKPASDEAPPGAGASVP
  PPLEAPPLVPKVPPRRKKSAPAAFHLQVLQSNSQLLQGLTYNSSDSPSGHPPAAGTVFPQ
  GDFLSTSSATSPDSDGTKAMKPEAAPLLGDYQDPFWNLLHHPKLLNNTWLSKSSDPLDSG
  TRSPKRDPIDPVSAGASAAKAELPPDHEHKTLGHWVTISDQEKRTALQVFDPLAKT
• Function: Inositol 5-phosphatase which may be involved in distinct membrane trafficking and signal transduction pathways. May mediate the inhibitory effect of Rac1 on endocytosis.
• KEGG Pathway:
  Inositol phosphate metabolism (hsa00562)
  Metabolic pathways (hsa01100)
  Phosphatidylinositol sig.ling system (hsa04070)
• Reactome Pathway:
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Synthesis of PIPs at the plasma membrane (R-HSA-1660499)
• BioCyc Pathway: MetaCyc:HS01279-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Hairy cell leukaemia	DISTD2E5	Strong	Genetic Variation	[5]
Joubert syndrome	DIS7P5CO	Strong	Biomarker	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[8]
Prostate neoplasm	DISHDKGQ	Strong	Genetic Variation	[3]
Endometriosis	DISX1AG8	moderate	Genetic Variation	[9]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Synaptojanin-2 (SYNJ2) affects the response to substance of Cisplatin.	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Synaptojanin-2 (SYNJ2).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Synaptojanin-2 (SYNJ2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Synaptojanin-2 (SYNJ2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Synaptojanin-2 (SYNJ2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Synaptojanin-2 (SYNJ2).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Synaptojanin-2 (SYNJ2).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Synaptojanin-2 (SYNJ2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Synaptojanin-2 (SYNJ2).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Synaptojanin-2 (SYNJ2).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Synaptojanin-2 (SYNJ2).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Synaptojanin-2 (SYNJ2).	[21]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Synaptojanin-2 (SYNJ2).	[22]
Selenium	DM25CGV	Approved	Selenium increases the expression of Synaptojanin-2 (SYNJ2).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Synaptojanin-2 (SYNJ2).	[24]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Synaptojanin-2 (SYNJ2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Synaptojanin-2 (SYNJ2).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Synaptojanin-2 (SYNJ2).	[16]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Synaptojanin-2 (SYNJ2).	[23]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Synaptojanin-2 (SYNJ2).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Synaptojanin-2 (SYNJ2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Synaptojanin-2 (SYNJ2).	[31]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Synaptojanin-2 (SYNJ2).	[32]

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 affects the phosphorylation of Synaptojanin-2 (SYNJ2).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Synaptojanin-2 (SYNJ2).	[30]

References

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• [2] Synaptojanin 2 is a druggable mediator of metastasis and the gene is overexpressed and amplified in breast cancer.Sci Signal. 2015 Jan 20;8(360):ra7. doi: 10.1126/scisignal.2005537.
• [3] Identification of inactivating mutations in the JAK1, SYNJ2, and CLPTM1 genes in prostate cancer cells using inhibition of nonsense-mediated decay and microarray analysis.Cancer Genet Cytogenet. 2005 Sep;161(2):97-103. doi: 10.1016/j.cancergencyto.2005.02.006.
• [4] SYNJ2 variant rs9365723 is associated with colorectal cancer risk in Chinese Han population.Int J Biol Markers. 2016 May 28;31(2):e138-43. doi: 10.5301/jbm.5000182.
• [5] Synaptojanin 2 is recognized by HLA class II-restricted hairy cell leukemia-specific T cells.Leukemia. 2003 Dec;17(12):2467-73. doi: 10.1038/sj.leu.2403174.
• [6] Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E.J Cell Sci. 2017 Feb 1;130(3):563-576. doi: 10.1242/jcs.197004. Epub 2016 Dec 7.
• [7] Synaptojanin 2 functions at an early step of clathrin-mediated endocytosis.Curr Biol. 2003 Apr 15;13(8):659-63. doi: 10.1016/s0960-9822(03)00241-0.
• [8] Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am J Hum Genet. 2017 Mar 2;100(3):523-536. doi: 10.1016/j.ajhg.2017.01.024. Epub 2017 Feb 9.
• [9] New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population-The genome-wide association study.Eur J Obstet Gynecol Reprod Biol. 2017 Oct;217:106-112. doi: 10.1016/j.ejogrb.2017.08.037. Epub 2017 Sep 1.
• [10] FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study.Eur J Hum Genet. 2017 Feb;25(3):324-331. doi: 10.1038/ejhg.2016.186. Epub 2017 Jan 4.
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• [13] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [14] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
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• [17] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [18] Gene expression profile changes in NB4 cells induced by arsenic trioxide. Acta Pharmacol Sin. 2003 Jul;24(7):646-50.
• [19] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [21] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [22] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [23] 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.
• [24] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [25] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [26] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [27] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [28] 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.
• [29] 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.
• [30] 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.
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• [32] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [33] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.