Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEFZB21)

• DOT Name: AP-2 complex subunit alpha-1 (AP2A1)
• Synonyms: 100 kDa coated vesicle protein A; Adaptor protein complex AP-2 subunit alpha-1; Adaptor-related protein complex 2 subunit alpha-1; Alpha-adaptin A; Alpha1-adaptin; Clathrin assembly protein complex 2 alpha-A large chain; Plasma membrane adaptor HA2/AP2 adaptin alpha A subunit
• Gene Name: AP2A1
• Related Disease:
  Acute myelogenous leukaemia
  Gastric neoplasm
  Thyroid gland papillary carcinoma
  Abdominal aortic aneurysm
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Cholangiocarcinoma
  Colorectal carcinoma
  Dermatitis
  Glioma
  Hepatocellular carcinoma
  Nasal polyp
  Neoplasm
  Zika virus infection
  Adenocarcinoma
  Lung cancer
  Lung carcinoma
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Rhabdomyosarcoma
  Squamous cell carcinoma
  Melanoma
  Branchiooculofacial syndrome
  Gastric cancer
  Stomach cancer
  Van der Woude syndrome
• UniProt ID: AP2A1_HUMAN
• Pfam ID: PF01602 ; PF02296 ; PF02883
• Sequence:
  MPAVSKGDGMRGLAVFISDIRNCKSKEAEIKRINKELANIRSKFKGDKALDGYSKKKYVC
  KLLFIFLLGHDIDFGHMEAVNLLSSNKYTEKQIGYLFISVLVNSNSELIRLINNAIKNDL
  ASRNPTFMCLALHCIANVGSREMGEAFAADIPRILVAGDSMDSVKQSAALCLLRLYKASP
  DLVPMGEWTARVVHLLNDQHMGVVTAAVSLITCLCKKNPDDFKTCVSLAVSRLSRIVSSA
  STDLQDYTYYFVPAPWLSVKLLRLLQCYPPPEDAAVKGRLVECLETVLNKAQEPPKSKKV
  QHSNAKNAILFETISLIIHYDSEPNLLVRACNQLGQFLQHRETNLRYLALESMCTLASSE
  FSHEAVKTHIDTVINALKTERDVSVRQRAADLLYAMCDRSNAKQIVSEMLRYLETADYAI
  REEIVLKVAILAEKYAVDYSWYVDTILNLIRIAGDYVSEEVWYRVLQIVTNRDDVQGYAA
  KTVFEALQAPACHENMVKVGGYILGEFGNLIAGDPRSSPPVQFSLLHSKFHLCSVATRAL
  LLSTYIKFINLFPETKATIQGVLRAGSQLRNADVELQQRAVEYLTLSSVASTDVLATVLE
  EMPPFPERESSILAKLKRKKGPGAGSALDDGRRDPSSNDINGGMEPTPSTVSTPSPSADL
  LGLRAAPPPAAPPASAGAGNLLVDVFDGPAAQPSLGPTPEEAFLSELEPPAPESPMALLA
  DPAPAADPGPEDIGPPIPEADELLNKFVCKNNGVLFENQLLQIGVKSEFRQNLGRMYLFY
  GNKTSVQFQNFSPTVVHPGDLQTQLAVQTKRVAAQVDGGAQVQQVLNIECLRDFLTPPLL
  SVRFRYGGAPQALTLKLPVTINKFFQPTEMAAQDFFQRWKQLSLPQQEAQKIFKANHPMD
  AEVTKAKLLGFGSALLDNVDPNPENFVGAGIIQTKALQVGCLLRLEPNAQAQMYRLTLRT
  SKEPVSRHLCELLAQQF
• 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 alpha subunit binds polyphosphoinositide-containing lipids, positioning AP-2 on the membrane. The AP-2 alpha subunit acts via its C-terminal appendage domain as a scaffolding platform for endocytic accessory proteins. The AP-2 alpha and AP-2 sigma subunits are thought to contribute to the recognition of the [ED]-X-X-X-L-[LI] motif.
• Tissue Specificity: Expressed in the brain (at protein level) . Isoform A: Expressed in forebrain, skeletal muscle, spinal cord, cerebellum, salivary gland, heart and colon. Isoform B: Widely expressed in tissues and also in breast cancer and in prostate carcinoma cells.
• 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)
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  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

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Gastric neoplasm	DISOKN4Y	Definitive	Biomarker	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Biomarker	[3]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[6]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[6]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Carcinoma	DISH9F1N	Strong	Altered Expression	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Dermatitis	DISY5SZC	Strong	Altered Expression	[11]
Glioma	DIS5RPEH	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Nasal polyp	DISLP3XE	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Zika virus infection	DISQUCTY	Strong	Biomarker	[15]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[16]
Lung cancer	DISCM4YA	moderate	Altered Expression	[17]
Lung carcinoma	DISTR26C	moderate	Altered Expression	[17]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[18]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[18]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[19]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[16]
Melanoma	DIS1RRCY	Disputed	Biomarker	[20]
Branchiooculofacial syndrome	DISHJ9O9	Limited	Genetic Variation	[21]
Gastric cancer	DISXGOUK	Limited	Biomarker	[5]
Stomach cancer	DISKIJSX	Limited	Biomarker	[5]
Van der Woude syndrome	DISADZS1	Limited	Genetic Variation	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of AP-2 complex subunit alpha-1 (AP2A1).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-2 complex subunit alpha-1 (AP2A1).	[24]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of AP-2 complex subunit alpha-1 (AP2A1).	[26]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of AP-2 complex subunit alpha-1 (AP2A1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of AP-2 complex subunit alpha-1 (AP2A1).	[29]

1 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 AP-2 complex subunit alpha-1 (AP2A1).	[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 alpha-1 (AP2A1).	[27]

References

• [1] Transcription factor AP-2 regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression.Int J Biochem Cell Biol. 2013 Aug;45(8):1647-56. doi: 10.1016/j.biocel.2013.04.024. Epub 2013 May 6.
• [2] Functions of the AP-2 gene in activating apoptosis and inhibiting proliferation of gastric cancer cells both in vitro and in vivo.Arch Med Sci. 2017 Oct;13(6):1255-1261. doi: 10.5114/aoms.2017.71064. Epub 2017 Oct 31.
• [3] AP-2 expression in papillary thyroid carcinoma predicts tumor progression and poor prognosis.Cancer Manag Res. 2018 Aug 13;10:2615-2625. doi: 10.2147/CMAR.S167874. eCollection 2018.
• [4] Pravastatin activates activator protein 2 alpha to augment the angiotensin II-induced abdominal aortic aneurysms.Oncotarget. 2017 Feb 28;8(9):14294-14305. doi: 10.18632/oncotarget.15104.
• [5] AP-2 reverses vincristine-induced multidrug resistance of SGC7901 gastric cancer cells by inhibiting the Notch pathway.Apoptosis. 2017 Jul;22(7):933-941. doi: 10.1007/s10495-017-1379-x.
• [6] Activation of activator protein 2 alpha by aspirin alleviates atherosclerotic plaque growth and instability in vivo.Oncotarget. 2016 Aug 16;7(33):52729-52739. doi: 10.18632/oncotarget.10400.
• [7] Protein-binding microarray analysis of tumor suppressor AP2 target gene specificity.PLoS One. 2011;6(8):e22895. doi: 10.1371/journal.pone.0022895. Epub 2011 Aug 18.
• [8] Reduced expression of transcription factor AP-2 is associated with gastric adenocarcinoma prognosis.PLoS One. 2011;6(9):e24897. doi: 10.1371/journal.pone.0024897. Epub 2011 Sep 26.
• [9] Role of AP-2 and MAPK7 in the regulation of autocrine TGF-/miR-200b signals to maintain epithelial-mesenchymal transition in cholangiocarcinoma.J Hematol Oncol. 2017 Oct 30;10(1):170. doi: 10.1186/s13045-017-0528-6.
• [10] Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/-catenin signalling pathway via suppression of activator protein 2.Gut. 2016 Sep;65(9):1494-504. doi: 10.1136/gutjnl-2014-308392. Epub 2015 May 20.
• [11] Molecular mechanism of kallikrein-related peptidase 8/neuropsin-induced hyperkeratosis in inflamed skin.Br J Dermatol. 2010 Sep;163(3):466-75. doi: 10.1111/j.1365-2133.2010.09864.x. Epub 2010 Aug 12.
• [12] The miR-26a/AP-2/Nanog signaling axis mediates stem cell self-renewal and temozolomide resistance in glioma.Theranostics. 2019 Jul 28;9(19):5497-5516. doi: 10.7150/thno.33800. eCollection 2019.
• [13] Long non-coding RNA CCAL promotes hepatocellular carcinoma progression by regulating AP-2 and Wnt/-catenin pathway.Int J Biol Macromol. 2018 Apr 1;109:424-434. doi: 10.1016/j.ijbiomac.2017.12.110. Epub 2017 Dec 22.
• [14] AP2alpha is essential for MUC8 gene expression in human airway epithelial cells.J Cell Biochem. 2010 Aug 15;110(6):1386-98. doi: 10.1002/jcb.22655.
• [15] Zika virus induces abnormal cranial osteogenesis by negatively affecting cranial neural crest development.Infect Genet Evol. 2019 Apr;69:176-189. doi: 10.1016/j.meegid.2019.01.023. Epub 2019 Jan 19.
• [16] Down-regulation of the polymeric immunoglobulin receptor in non-small cell lung carcinoma: correlation with dysregulated expression of the transcription factors USF and AP2.J Biomed Sci. 2005;12(1):65-77. doi: 10.1007/s11373-004-8185-5.
• [17] AP-2 downregulation by cigarette smoke condensate is counteracted by p53 in human lung cancer cells.Int J Mol Med. 2014 Oct;34(4):1094-100. doi: 10.3892/ijmm.2014.1857. Epub 2014 Jul 17.
• [18] Aberrant expressions of AP-2 splice variants in pancreatic cancer.Pancreas. 2011 Jul;40(5):695-700. doi: 10.1097/MPA.0b013e31821f2715.
• [19] The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71.J Biol Chem. 2011 Jan 7;286(1):309-21. doi: 10.1074/jbc.M110.168468. Epub 2010 Oct 18.
• [20] AP2 controls the dynamic balance between miR-126&126* and miR-221&222 during melanoma progression.Oncogene. 2016 Jun 9;35(23):3016-26. doi: 10.1038/onc.2015.357. Epub 2015 Oct 5.
• [21] Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2 DNA-binding domain.Hum Mol Genet. 2013 Aug 15;22(16):3195-206. doi: 10.1093/hmg/ddt173. Epub 2013 Apr 10.
• [22] Association and Mutation Analyses of the IRF6 Gene in Families With Nonsyndromic and Syndromic Cleft Lip and/or Cleft Palate.Cleft Palate Craniofac J. 2014 Jan;51(1):49-55. doi: 10.1597/11-220. Epub 2013 Feb 8.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [27] 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.
• [28] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [29] 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.