Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8VR95S)

• DOT Name: DCC-interacting protein 13-alpha (APPL1)
• Synonyms: Dip13-alpha; Adapter protein containing PH domain, PTB domain and leucine zipper motif 1
• Gene Name: APPL1
• Related Disease:
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Hyperglycemia
  Maturity-onset diabetes of the young type 14
  Non-alcoholic fatty liver disease
  Oculocerebrorenal syndrome
  Polycystic ovarian syndrome
  Prostate cancer
  Prostate carcinoma
  Renal fibrosis
  Type-1/2 diabetes
  Advanced cancer
  Obesity
  Stomach cancer
  Maturity-onset diabetes of the young
  Coronary atherosclerosis
  Coronary heart disease
  Monogenic diabetes
  Neoplasm
  Non-insulin dependent diabetes
  Subarachnoid hemorrhage
  Type-1 diabetes
• UniProt ID: DP13A_HUMAN
• PDB ID: 2EJ8; 2ELA; 2ELB; 2Q12; 2Q13; 2Z0N; 2Z0O; 5C5B
• Pfam ID: PF16746 ; PF00169 ; PF00640
• Sequence:
  MPGIDKLPIEETLEDSPQTRSLLGVFEEDATAISNYMNQLYQAMHRIYDAQNELSAATHL
  TSKLLKEYEKQRFPLGGDDEVMSSTLQQFSKVIDELSSCHAVLSTQLADAMMFPITQFKE
  RDLKEILTLKEVFQIASNDHDAAINRYSRLSKKRENDKVKYEVTEDVYTSRKKQHQTMMH
  YFCALNTLQYKKKIALLEPLLGYMQAQISFFKMGSENLNEQLEEFLANIGTSVQNVRREM
  DSDIETMQQTIEDLEVASDPLYVPDPDPTKFPVNRNLTRKAGYLNARNKTGLVSSTWDRQ
  FYFTQGGNLMSQARGDVAGGLAMDIDNCSVMAVDCEDRRYCFQITSFDGKKSSILQAESK
  KDHEEWICTINNISKQIYLSENPEETAARVNQSALEAVTPSPSFQQRHESLRPAAGQSRP
  PTARTSSSGSLGSESTNLAALSLDSLVAPDTPIQFDIISPVCEDQPGQAKAFGQGGRRTN
  PFGESGGSTKSETEDSILHQLFIVRFLGSMEVKSDDHPDVVYETMRQILAARAIHNIFRM
  TESHLLVTCDCLKLIDPQTQVTRLTFPLPCVVLYATHQENKRLFGFVLRTSSGRSESNLS
  SVCYIFESNNEGEKICDSVGLAKQIALHAELDRRASEKQKEIERVKEKQQKELNKQKQIE
  KDLEEQSRLIAASSRPNQASSEGQFVVLSSSQSEESDLGEGGKKRESEA
• Function: Multifunctional adapter protein that binds to various membrane receptors, nuclear factors and signaling proteins to regulate many processes, such as cell proliferation, immune response, endosomal trafficking and cell metabolism. Regulates signaling pathway leading to cell proliferation through interaction with RAB5A and subunits of the NuRD/MeCP1 complex. Functions as a positive regulator of innate immune response via activation of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1. Inhibits Fc-gamma receptor-mediated phagocytosis through PI3K/Akt signaling in macrophages. Regulates TLR4 signaling in activated macrophages. Involved in trafficking of the TGFBR1 from the endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Plays a role in cell metabolism by regulating adiponecting and insulin signaling pathways. Required for fibroblast migration through HGF cell signaling. Positive regulator of beta-catenin/TCF-dependent transcription through direct interaction with RUVBL2/reptin resulting in the relief of RUVBL2-mediated repression of beta-catenin/TCF target genes by modulating the interactions within the beta-catenin-reptin-HDAC complex.
• Tissue Specificity: High levels in heart, ovary, pancreas and skeletal muscle.
• KEGG Pathway:
  Longevity regulating pathway (hsa04211)
  Adipocytokine sig.ling pathway (hsa04920)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
• Reactome Pathway: Caspase activation via Dependence Receptors in the absence of ligand (R-HSA-418889)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[5]
Maturity-onset diabetes of the young type 14	DISY6886	Strong	Autosomal dominant	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[7]
Oculocerebrorenal syndrome	DIS8TEDY	Strong	Biomarker	[8]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[10]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[11]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[12]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[13]
Obesity	DIS47Y1K	moderate	Biomarker	[14]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[15]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[16]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[17]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[17]
Monogenic diabetes	DISEB8Q0	Limited	Autosomal dominant	[18]
Neoplasm	DISZKGEW	Limited	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[17]
Subarachnoid hemorrhage	DISI7I8Y	Limited	Biomarker	[20]
Type-1 diabetes	DIS7HLUB	Limited	Altered Expression	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of DCC-interacting protein 13-alpha (APPL1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DCC-interacting protein 13-alpha (APPL1).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DCC-interacting protein 13-alpha (APPL1).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DCC-interacting protein 13-alpha (APPL1).	[25]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of DCC-interacting protein 13-alpha (APPL1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DCC-interacting protein 13-alpha (APPL1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DCC-interacting protein 13-alpha (APPL1).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of DCC-interacting protein 13-alpha (APPL1).	[31]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of DCC-interacting protein 13-alpha (APPL1).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of DCC-interacting protein 13-alpha (APPL1).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of DCC-interacting protein 13-alpha (APPL1).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DCC-interacting protein 13-alpha (APPL1).	[32]

References

• [1] Evidence that the rab5 effector APPL1 mediates APP-CTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease.Mol Psychiatry. 2016 May;21(5):707-16. doi: 10.1038/mp.2015.97. Epub 2015 Jul 21.
• [2] Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses.Atherosclerosis. 2012 Mar;221(1):66-75. doi: 10.1016/j.atherosclerosis.2011.12.014. Epub 2011 Dec 22.
• [3] APPL proteins promote TGF-induced nuclear transport of the TGF type I receptor intracellular domain.Oncotarget. 2016 Jan 5;7(1):279-92. doi: 10.18632/oncotarget.6346.
• [4] Experimental verification of a predicted novel microRNA located in human PIK3CA gene with a potential oncogenic function in colorectal cancer.Tumour Biol. 2016 Oct;37(10):14089-14101. doi: 10.1007/s13277-016-5264-y. Epub 2016 Aug 10.
• [5] Increased abundance of the adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif (APPL1) in patients with obesity and type 2 diabetes: evidence for altered adiponectin signalling.Diabetologia. 2011 Aug;54(8):2122-31. doi: 10.1007/s00125-011-2173-x. Epub 2011 May 12.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.PLoS One. 2013 Aug 19;8(8):e71391. doi: 10.1371/journal.pone.0071391. eCollection 2013.
• [8] Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1.Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3511-6. doi: 10.1073/pnas.0914658107. Epub 2010 Feb 2.
• [9] Evidence for decreased expression of APPL1 associated with reduced insulin and adiponectin receptors expression in PCOS patients.J Endocrinol Invest. 2016 Sep;39(9):1075-82. doi: 10.1007/s40618-016-0468-y. Epub 2016 Apr 13.
• [10] The function of oxytocin: a potential biomarker for prostate cancer diagnosis and promoter of prostate cancer.Oncotarget. 2017 May 9;8(19):31215-31226. doi: 10.18632/oncotarget.16107.
• [11] Curcumin alleviates ischemia reperfusion-induced late kidney fibrosis through the APPL1/Akt signaling pathway.J Cell Physiol. 2018 Nov;233(11):8588-8596. doi: 10.1002/jcp.26536. Epub 2018 May 9.
• [12] APPLs: More than just adiponectin receptor binding proteins.Cell Signal. 2017 Apr;32:76-84. doi: 10.1016/j.cellsig.2017.01.018. Epub 2017 Jan 17.
• [13] 51 integrin trafficking and Rac activation are regulated by APPL1 in a Rab5-dependent manner to inhibit cell migration.J Cell Sci. 2018 Mar 6;131(5):jcs207019. doi: 10.1242/jcs.207019.
• [14] Adaptor protein APPL1 coordinates HDAC3 to modulate brown adipose tissue thermogenesis in mice.Metabolism. 2019 Nov;100:153955. doi: 10.1016/j.metabol.2019.153955. Epub 2019 Aug 4.
• [15] APPL1 promotes the migration of gastric cancer cells by regulating Akt2 phosphorylation.Int J Oncol. 2017 Oct;51(4):1343-1351. doi: 10.3892/ijo.2017.4121. Epub 2017 Sep 5.
• [16] Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. Am J Hum Genet. 2015 Jul 2;97(1):177-85. doi: 10.1016/j.ajhg.2015.05.011. Epub 2015 Jun 11.
• [17] Genetic variability in adapter proteins with APPL1/2 is associated with the risk of coronary artery disease in type 2 diabetes mellitus in Chinese Han population.Chin Med J (Engl). 2011 Nov;124(22):3618-21.
• [18] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [19] Altered endosome biogenesis in prostate cancer has biomarker potential.Mol Cancer Res. 2014 Dec;12(12):1851-62. doi: 10.1158/1541-7786.MCR-14-0074. Epub 2014 Jul 30.
• [20] Intranasal administration of recombinant Netrin-1 attenuates neuronal apoptosis by activating DCC/APPL-1/AKT signaling pathway after subarachnoid hemorrhage in rats.Neuropharmacology. 2017 Jun;119:123-133. doi: 10.1016/j.neuropharm.2017.03.025. Epub 2017 Mar 24.
• [21] APPL1 prevents pancreatic beta cell death and inflammation by dampening NFB activation in a mouse model of type 1 diabetes.Diabetologia. 2017 Mar;60(3):464-474. doi: 10.1007/s00125-016-4185-z. Epub 2016 Dec 23.
• [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] 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.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] 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.
• [27] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [28] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [29] 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.
• [30] 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.
• [31] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [32] 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.
• [33] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.