Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTFE53M)

• DOT Name: Amyloid beta precursor like protein 2 (APLP2)
• Synonyms: APPH; Amyloid beta (A4) precursor-like protein 2; Amyloid protein homolog; Amyloid-like protein 2; APLP-2; CDEI box-binding protein; CDEBP; Sperm membrane protein YWK-II
• Gene Name: APLP2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease 3
  Amyloidosis
  Glioblastoma multiforme
  Glioma
  Metastatic malignant neoplasm
  Myocardial ischemia
  Neuroblastoma
  Pancreatic tumour
  Refractive error
  Alzheimer disease
  Neoplasm
  Neurodegenerative disease
  Obesity
  Thyroid gland follicular carcinoma
  Autosomal dominant cerebellar ataxia type II
  Clear cell renal carcinoma
  Pancreatic cancer
  Renal cell carcinoma
• UniProt ID: APLP2_HUMAN
• PDB ID: 5JBT; 5TPT
• Pfam ID: PF10515 ; PF12924 ; PF12925 ; PF02177 ; PF00014
• Sequence:
  MAATGTAAAAATGRLLLLLLVGLTAPALALAGYIEALAANAGTGFAVAEPQIAMFCGKLN
  MHVNIQTGKWEPDPTGTKSCFETKEEVLQYCQEMYPELQITNVMEANQRVSIDNWCRRDK
  KQCKSRFVTPFKCLVGEFVSDVLLVPEKCQFFHKERMEVCENHQHWHTVVKEACLTQGMT
  LYSYGMLLPCGVDQFHGTEYVCCPQTKIIGSVSKEEEEEDEEEEEEEDEEEDYDVYKSEF
  PTEADLEDFTEAAVDEDDEDEEEGEEVVEDRDYYYDTFKGDDYNEENPTEPGSDGTMSDK
  EITHDVKAVCSQEAMTGPCRAVMPRWYFDLSKGKCVRFIYGGCGGNRNNFESEDYCMAVC
  KAMIPPTPLPTNDVDVYFETSADDNEHARFQKAKEQLEIRHRNRMDRVKKEWEEAELQAK
  NLPKAERQTLIQHFQAMVKALEKEAASEKQQLVETHLARVEAMLNDRRRMALENYLAALQ
  SDPPRPHRILQALRRYVRAENKDRLHTIRHYQHVLAVDPEKAAQMKSQVMTHLHVIEERR
  NQSLSLLYKVPYVAQEIQEEIDELLQEQRADMDQFTASISETPVDVRVSSEESEEIPPFH
  PFHPFPALPENEDTQPELYHPMKKGSGVGEQDGGLIGAEEKVINSKNKVDENMVIDETLD
  VKEMIFNAERVGGLEEERESVGPLREDFSLSSSALIGLLVIAVAIATVIVISLVMLRKRQ
  YGTISHGIVEVDPMLTPEERHLNKMQNHGYENPTYKYLEQMQI
• Function: May play a role in the regulation of hemostasis. The soluble form may have inhibitory properties towards coagulation factors. May interact with cellular G-protein signaling pathways. May bind to the DNA 5'-GTCACATG-3'(CDEI box). Inhibits trypsin, chymotrypsin, plasmin, factor XIA and plasma and glandular kallikrein. Modulates the Cu/Zn nitric oxide-catalyzed autodegradation of GPC1 heparan sulfate side chains in fibroblasts.
• Tissue Specificity: Expressed in placenta, brain, heart, lung, liver, kidney and endothelial tissues.
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease 3	DISVT69G	Strong	Biomarker	[3]
Amyloidosis	DISHTAI2	Strong	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[4]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[5]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[6]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[4]
Refractive error	DISWNEQ1	Strong	Genetic Variation	[7]
Alzheimer disease	DISF8S70	moderate	Biomarker	[8]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[9]
Obesity	DIS47Y1K	moderate	Biomarker	[10]
Thyroid gland follicular carcinoma	DISFK2QT	moderate	Biomarker	[11]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Biomarker	[12]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[13]
Pancreatic cancer	DISJC981	Limited	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Amyloid beta precursor like protein 2 (APLP2) affects the response to substance of Paclitaxel.	[33]

19 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 Amyloid beta precursor like protein 2 (APLP2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Amyloid beta precursor like protein 2 (APLP2).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Amyloid beta precursor like protein 2 (APLP2).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Amyloid beta precursor like protein 2 (APLP2).	[22]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[23]
Selenium	DM25CGV	Approved	Selenium increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[24]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Amyloid beta precursor like protein 2 (APLP2).	[25]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[26]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Amyloid beta precursor like protein 2 (APLP2).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Amyloid beta precursor like protein 2 (APLP2).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[30]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of Amyloid beta precursor like protein 2 (APLP2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Amyloid beta precursor like protein 2 (APLP2).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the secretion of Amyloid beta precursor like protein 2 (APLP2).	[6]
GM6001	DM7V9CT	Discontinued in Phase 2	GM6001 decreases the secretion of Amyloid beta precursor like protein 2 (APLP2).	[6]

1 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 Amyloid beta precursor like protein 2 (APLP2).	[31]

References

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• [2] The crystal structure of amyloid precursor-like protein 2 E2 domain completes the amyloid precursor protein family.FASEB J. 2019 Apr;33(4):5076-5081. doi: 10.1096/fj.201802315R. Epub 2019 Jan 4.
• [3] Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3beta expression.Cell Death Differ. 2007 Jan;14(1):79-91. doi: 10.1038/sj.cdd.4401928. Epub 2006 Apr 28.
• [4] Amyloid precursor-like protein 2 (APLP2) affects the actin cytoskeleton and increases pancreatic cancer growth and metastasis.Oncotarget. 2015 Feb 10;6(4):2064-75. doi: 10.18632/oncotarget.2990.
• [5] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [6] Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. FEBS J. 2005 Nov;272(22):5808-20. doi: 10.1111/j.1742-4658.2005.04976.x.
• [7] APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans.PLoS Genet. 2015 Aug 27;11(8):e1005432. doi: 10.1371/journal.pgen.1005432. eCollection 2015 Aug.
• [8] MicroRNA-153 negatively regulates the expression of amyloid precursor protein and amyloid precursor-like protein 2.Brain Res. 2012 May 21;1455:103-13. doi: 10.1016/j.brainres.2011.10.051. Epub 2011 Nov 4.
• [9] Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein.J Neurosci. 2002 Jan 15;22(2):365-76. doi: 10.1523/JNEUROSCI.22-02-00365.2002.
• [10] Protein hydrolysate from potato confers hepatic-protection in hamsters against high fat diet induced apoptosis and fibrosis by suppressing Caspase-3 and MMP2/9 and by enhancing Akt-survival pathway.BMC Complement Altern Med. 2019 Oct 25;19(1):283. doi: 10.1186/s12906-019-2700-8.
• [11] APLP2, RRM2, and PRC1: New Putative Markers for the Differential Diagnosis of Thyroid Follicular Lesions.Thyroid. 2017 Jan;27(1):59-66. doi: 10.1089/thy.2016.0094. Epub 2016 Nov 30.
• [12] Amyloid precursor-like protein 2 cleavage contributes to neuronal intranuclear inclusions and cytotoxicity in spinocerebellar ataxia-7 (SCA7).Neurobiol Dis. 2011 Jan;41(1):33-42. doi: 10.1016/j.nbd.2010.08.016. Epub 2010 Aug 20.
• [13] Role of APLP2 in the prognosis and clinicopathology of renal cell carcinoma.Oncol Lett. 2019 Jan;17(1):508-513. doi: 10.3892/ol.2018.9577. Epub 2018 Oct 15.
• [14] An Integrative Data Mining and Omics-Based Translational Model for the Identification and Validation of Oncogenic Biomarkers of Pancreatic Cancer.Cancers (Basel). 2019 Jan 29;11(2):155. doi: 10.3390/cancers11020155.
• [15] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [16] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [17] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [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] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [22] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [23] Gene induction and apoptosis in human hepatocellular carci-noma cells SMMC-7721 exposed to 5-aza-2'-deoxycytidine. Chin Med J (Engl). 2007 Sep 20;120(18):1626-31.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases. FEBS J. 2005 Nov;272(22):5808-20. doi: 10.1111/j.1742-4658.2005.04976.x.
• [30] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [31] 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.
• [32] 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.
• [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.