Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9S4C4K)

• DOT Name: DCC-interacting protein 13-beta (APPL2)
• Synonyms: Dip13-beta; Adapter protein containing PH domain, PTB domain and leucine zipper motif 2
• Gene Name: APPL2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Colorectal carcinoma
  Depression
  Drug dependence
  Glioblastoma multiforme
  Glioma
  Mental disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Prostate cancer
  Prostate neoplasm
  Substance abuse
  Substance dependence
  Coronary heart disease
  Non-insulin dependent diabetes
• UniProt ID: DP13B_HUMAN
• PDB ID: 4H8S; 5C5B
• Pfam ID: PF16746 ; PF00169 ; PF00640
• Sequence:
  MPAVDKLLLEEALQDSPQTRSLLSVFEEDAGTLTDYTNQLLQAMQRVYGAQNEMCLATQQ
  LSKQLLAYEKQNFALGKGDEEVISTLHYFSKVVDELNLLHTELAKQLADTMVLPIIQFRE
  KDLTEVSTLKDLFGLASNEHDLSMAKYSRLPKKKENEKVKTEVGKEVAAARRKQHLSSLQ
  YYCALNALQYRKQMAMMEPMIGFAHGQINFFKKGAEMFSKRMDSFLSSVADMVQSIQVEL
  EAEAEKMRVSQQELLSVDESVYTPDSDVAAPQINRNLIQKAGYLNLRNKTGLVTTTWERL
  YFFTQGGNLMCQPRGAVAGGLIQDLDNCSVMAVDCEDRRYCFQITTPNGKSGIILQAESR
  KENEEWICAINNISRQIYLTDNPEAVAIKLNQTALQAVTPITSFGKKQESSCPSQNLKNS
  EMENENDKIVPKATASLPEAEELIAPGTPIQFDIVLPATEFLDQNRGSRRTNPFGETEDE
  SFPEAEDSLLQQMFIVRFLGSMAVKTDSTTEVIYEAMRQVLAARAIHNIFRMTESHLMVT
  SQSLRLIDPQTQVSRANFELTSVTQFAAHQENKRLVGFVIRVPESTGEESLSTYIFESNS
  EGEKICYAINLGKEIIEVQKDPEALAQLMLSIPLTNDGKYVLLNDQPDDDDGNPNEHRGA
  ESEA
• 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. Plays a role in immune response by modulating phagocytosis, inflammatory and innate immune responses. In macrophages, enhances Fc-gamma receptor-mediated phagocytosis through interaction with RAB31 leading to activation of PI3K/Akt signaling. In response to LPS, modulates inflammatory responses by playing a key role on the regulation of TLR4 signaling and in the nuclear translocation of RELA/NF-kappa-B p65 and the secretion of pro- and anti-inflammatory cytokines. Also functions as a negative regulator of innate immune response via inhibition of AKT1 signaling pathway by forming a complex with APPL1 and PIK3R1. Plays a role in endosomal trafficking of TGFBR1 from the endosomes to the nucleus. Plays a role in cell metabolism by regulating adiponecting ans insulin signaling pathways and adaptative thermogenesis. In muscle, negatively regulates adiponectin-simulated glucose uptake and fatty acid oxidation by inhibiting adiponectin signaling pathway through APPL1 sequestration thereby antagonizing APPL1 action. In muscles, negativeliy regulates insulin-induced plasma membrane recruitment of GLUT4 and glucose uptake through interaction with TBC1D1. Plays a role in cold and diet-induced adaptive thermogenesis by activating ventromedial hypothalamus (VMH) neurons throught AMPK inhibition which enhances sympathetic outflow to subcutaneous white adipose tissue (sWAT), sWAT beiging and cold tolerance. Also plays a role in other signaling pathways namely Wnt/beta-catenin, HGF and glucocorticoid receptor 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. May affect adult neurogenesis in hippocampus and olfactory system via regulating the sensitivity of glucocorticoid receptor. Required for fibroblast migration through HGF cell signaling.
• Tissue Specificity: High levels in brain, heart, kidney and skeletal muscle.

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]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Drug dependence	DIS9IXRC	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Mental disorder	DIS3J5R8	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Substance abuse	DIS327VW	Strong	Biomarker	[5]
Substance dependence	DISDRAAR	Strong	Biomarker	[5]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DCC-interacting protein 13-beta (APPL2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DCC-interacting protein 13-beta (APPL2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DCC-interacting protein 13-beta (APPL2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DCC-interacting protein 13-beta (APPL2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DCC-interacting protein 13-beta (APPL2).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DCC-interacting protein 13-beta (APPL2).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DCC-interacting protein 13-beta (APPL2).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of DCC-interacting protein 13-beta (APPL2).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DCC-interacting protein 13-beta (APPL2).	[18]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of DCC-interacting protein 13-beta (APPL2).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of DCC-interacting protein 13-beta (APPL2).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DCC-interacting protein 13-beta (APPL2).	[21]

References

• [1] Multifunctional protein APPL2 contributes to survival of human glioma cells.Mol Oncol. 2013 Feb;7(1):67-84. doi: 10.1016/j.molonc.2012.08.003. Epub 2012 Sep 5.
• [2] 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.
• [3] Overexpressed in colorectal carcinoma gene (OCC-1) upregulation and APPL2 gene downregulation in breast cancer specimens.Mol Biol Rep. 2018 Dec;45(6):1889-1895. doi: 10.1007/s11033-018-4336-z. Epub 2018 Sep 14.
• [4] Baicalin Modulates APPL2/Glucocorticoid Receptor Signaling Cascade, Promotes Neurogenesis, and Attenuates Emotional and Olfactory Dysfunctions in Chronic Corticosterone-Induced Depression.Mol Neurobiol. 2018 Dec;55(12):9334-9348. doi: 10.1007/s12035-018-1042-8. Epub 2018 Apr 19.
• [5] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [6] Adaptor Protein APPL2 Affects Adult Antidepressant Behaviors and Hippocampal Neurogenesis via Regulating the Sensitivity of Glucocorticoid Receptor.Mol Neurobiol. 2018 Jul;55(7):5537-5547. doi: 10.1007/s12035-017-0785-y. Epub 2017 Sep 30.
• [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] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [9] 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.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [17] 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.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.