Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL6LZJ4)

• DOT Name: AP-2 complex subunit beta (AP2B1)
• Synonyms: AP105B; Adaptor protein complex AP-2 subunit beta; Adaptor-related protein complex 2 subunit beta; Beta-2-adaptin; Beta-adaptin; Clathrin assembly protein complex 2 beta large chain; Plasma membrane adaptor HA2/AP2 adaptin beta subunit
• Gene Name: AP2B1
• Related Disease:
  Cerebellar degeneration
  Meningioma
  Advanced cancer
  Depression
  Ductal breast carcinoma in situ
  Glaucoma/ocular hypertension
  Hepatocellular carcinoma
  Hereditary glaucoma
  Mood disorder
  Schizophrenia
  Alcohol dependence
  Neoplasm
  Rhabdomyosarcoma
  Breast cancer
  Breast carcinoma
• UniProt ID: AP2B1_HUMAN
• PDB ID: 1E42; 2G30; 2IV8; 2IV9; 2JKR; 2JKT; 2VGL; 2XA7; 4UQI; 5M5R; 6QH5; 6QH6; 6QH7; 6URI; 6YAE; 6YAF; 6YAH; 6YAI; 7OG1; 7OHO; 7OM8; 7Z5C
• Pfam ID: PF01602 ; PF02883 ; PF09066
• Sequence:
  MTDSKYFTTNKKGEIFELKAELNNEKKEKRKEAVKKVIAAMTVGKDVSSLFPDVVNCMQT
  DNLELKKLVYLYLMNYAKSQPDMAIMAVNSFVKDCEDPNPLIRALAVRTMGCIRVDKITE
  YLCEPLRKCLKDEDPYVRKTAAVCVAKLHDINAQMVEDQGFLDSLRDLIADSNPMVVANA
  VAALSEISESHPNSNLLDLNPQNINKLLTALNECTEWGQIFILDCLSNYNPKDDREAQSI
  CERVTPRLSHANSAVVLSAVKVLMKFLELLPKDSDYYNMLLKKLAPPLVTLLSGEPEVQY
  VALRNINLIVQKRPEILKQEIKVFFVKYNDPIYVKLEKLDIMIRLASQANIAQVLAELKE
  YATEVDVDFVRKAVRAIGRCAIKVEQSAERCVSTLLDLIQTKVNYVVQEAIVVIRDIFRK
  YPNKYESIIATLCENLDSLDEPDARAAMIWIVGEYAERIDNADELLESFLEGFHDESTQV
  QLTLLTAIVKLFLKKPSETQELVQQVLSLATQDSDNPDLRDRGYIYWRLLSTDPVTAKEV
  VLSEKPLISEETDLIEPTLLDELICHIGSLASVYHKPPNAFVEGSHGIHRKHLPIHHGST
  DAGDSPVGTTTATNLEQPQVIPSQGDLLGDLLNLDLGPPVNVPQVSSMQMGAVDLLGGGL
  DSLVGQSFIPSSVPATFAPSPTPAVVSSGLNDLFELSTGIGMAPGGYVAPKAVWLPAVKA
  KGLEISGTFTHRQGHIYMEMNFTNKALQHMTDFAIQFNKNSFGVIPSTPLAIHTPLMPNQ
  SIDVSLPLNTLGPVMKMEPLNNLQVAVKNNIDVFYFSCLIPLNVLFVEDGKMERQVFLAT
  WKDIPNENELQFQIKECHLNADTVSSKLQNNNVYTIAKRNVEGQDMLYQSLKLTNGIWIL
  AELRIQPGNPNYTLSLKCRAPEVSQYIYQVYDSILKN
• Function: Component of the adaptor protein complex 2 (AP-2). Adaptor protein complexes function in protein transport via transport vesicles in different membrane traffic pathways. Adaptor protein complexes are vesicle coat components and appear to be involved in cargo selection and vesicle formation. AP-2 is involved in clathrin-dependent endocytosis in which cargo proteins are incorporated into vesicles surrounded by clathrin (clathrin-coated vesicles, CCVs) which are destined for fusion with the early endosome. The clathrin lattice serves as a mechanical scaffold but is itself unable to bind directly to membrane components. Clathrin-associated adaptor protein (AP) complexes which can bind directly to both the clathrin lattice and to the lipid and protein components of membranes are considered to be the major clathrin adaptors contributing the CCV formation. AP-2 also serves as a cargo receptor to selectively sort the membrane proteins involved in receptor-mediated endocytosis. AP-2 seems to play a role in the recycling of synaptic vesicle membranes from the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi) and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the cytosolic tails of transmembrane cargo molecules. AP-2 may also play a role in maintaining normal post-endocytic trafficking through the ARF6-regulated, non-clathrin pathway. During long-term potentiation in hippocampal neurons, AP-2 is responsible for the endocytosis of ADAM10. The AP-2 beta subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins; at least some clathrin-associated sorting proteins (CLASPs) are recognized by their [DE]-X(1,2)-F-X-X-[FL]-X-X-X-R motif. The AP-2 beta subunit binds to clathrin heavy chain, promoting clathrin lattice assembly; clathrin displaces at least some CLASPs from AP2B1 which probably then can be positioned for further coat assembly.
• Tissue Specificity: Expressed in the brain (at protein level).
• KEGG Pathway:
  Endocytosis (hsa04144)
  Sy.ptic vesicle cycle (hsa04721)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Retrograde neurotrophin signalling (R-HSA-177504)
  Nef Mediated CD8 Down-regulation (R-HSA-182218)
  MHC class II antigen presentation (R-HSA-2132295)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  Recycling pathway of L1 (R-HSA-437239)
  WNT5A-dependent internalization of FZD4 (R-HSA-5099900)
  WNT5A-dependent internalization of FZD2, FZD5 and ROR2 (R-HSA-5140745)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  VLDLR internalisation and degradation (R-HSA-8866427)
  LDL clearance (R-HSA-8964038)
  Potential therapeutics for SARS (R-HSA-9679191)
  Nef Mediated CD4 Down-regulation (R-HSA-167590)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar degeneration	DISPBCM3	Definitive	Biomarker	[1]
Meningioma	DISPT4TG	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Depression	DIS3XJ69	Strong	Genetic Variation	[4]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[5]
Glaucoma/ocular hypertension	DISLBXBY	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Hereditary glaucoma	DISJYSR1	Strong	Altered Expression	[6]
Mood disorder	DISLVMWO	Strong	Biomarker	[8]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[9]
Alcohol dependence	DIS4ZSCO	moderate	Biomarker	[10]
Neoplasm	DISZKGEW	moderate	Biomarker	[5]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[11]
Breast cancer	DIS7DPX1	Disputed	Biomarker	[5]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Indinavir	DM0T3YH	Approved	AP-2 complex subunit beta (AP2B1) increases the Insulin resistance ADR of Indinavir.	[27]

13 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 AP-2 complex subunit beta (AP2B1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of AP-2 complex subunit beta (AP2B1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-2 complex subunit beta (AP2B1).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of AP-2 complex subunit beta (AP2B1).	[15]
Marinol	DM70IK5	Approved	Marinol increases the expression of AP-2 complex subunit beta (AP2B1).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of AP-2 complex subunit beta (AP2B1).	[17]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of AP-2 complex subunit beta (AP2B1).	[18]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of AP-2 complex subunit beta (AP2B1).	[19]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of AP-2 complex subunit beta (AP2B1).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of AP-2 complex subunit beta (AP2B1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of AP-2 complex subunit beta (AP2B1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of AP-2 complex subunit beta (AP2B1).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of AP-2 complex subunit beta (AP2B1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of AP-2 complex subunit beta (AP2B1).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of AP-2 complex subunit beta (AP2B1).	[26]

References

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• [3] DHX33 Interacts with AP-2 To Regulate Bcl-2 Gene Expression and Promote Cancer Cell Survival.Mol Cell Biol. 2019 Aug 12;39(17):e00017-19. doi: 10.1128/MCB.00017-19. Print 2019 Sep 1.
• [4] Transcription factor AP-2 beta genotype and psychosocial adversity in relation to adolescent depressive symptomatology.J Neural Transm (Vienna). 2009 Mar;116(3):363-70. doi: 10.1007/s00702-009-0183-3. Epub 2009 Jan 28.
• [5] Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2.Lab Invest. 2018 Jan;98(1):117-129. doi: 10.1038/labinvest.2017.106. Epub 2017 Oct 16.
• [6] Generation of a new mouse model of glaucoma characterized by reduced expression of the AP-2 and AP-2 proteins.Sci Rep. 2017 Sep 11;7(1):11140. doi: 10.1038/s41598-017-11752-6.
• [7] AP-2 inhibits hepatocellular carcinoma invasion and metastasis through Slug and Snail to suppress epithelial-mesenchymal transition.Theranostics. 2018 Jun 12;8(13):3707-3721. doi: 10.7150/thno.25166. eCollection 2018.
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• [9] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [10] Transcription factor AP2 beta involved in severe female alcoholism.Brain Res. 2009 Dec 11;1305 Suppl:S20-6. doi: 10.1016/j.brainres.2009.09.054. Epub 2009 Sep 22.
• [11] DAX-1 Expression in Pediatric Rhabdomyosarcomas: Another Immunohistochemical Marker Useful in the Diagnosis of Translocation Positive Alveolar Rhabdomyosarcoma.PLoS One. 2015 Jul 13;10(7):e0133019. doi: 10.1371/journal.pone.0133019. eCollection 2015.
• [12] 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.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] 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.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [20] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [23] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] 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.
• [27] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.