Details of Drug Off-Target (DOT)

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

• DOT Name: AP-2 complex subunit mu (AP2M1)
• Synonyms: AP-2 mu chain; Adaptin-mu2; Adaptor protein complex AP-2 subunit mu; Adaptor-related protein complex 2 subunit mu; Clathrin assembly protein complex 2 mu medium chain; Clathrin coat assembly protein AP50; Clathrin coat-associated protein AP50; HA2 50 kDa subunit; Plasma membrane adaptor AP-2 50 kDa protein
• Gene Name: AP2M1
• Related Disease:
  Advanced cancer
  Epilepsy
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Influenza
  Intellectual developmental disorder 60 with seizures
  Intellectual disability
  Lung squamous cell carcinoma
  Meningococcal disease
  Squamous cell carcinoma
  Myoclonic-astatic epilepsy
• UniProt ID: AP2M1_HUMAN
• PDB ID: 1H6E; 6BNT; 6URI
• Pfam ID: PF00928 ; PF01217
• Sequence:
  MIGGLFIYNHKGEVLISRVYRDDIGRNAVDAFRVNVIHARQQVRSPVTNIARTSFFHVKR
  SNIWLAAVTKQNVNAAMVFEFLYKMCDVMAAYFGKISEENIKNNFVLIYELLDEILDFGY
  PQNSETGALKTFITQQGIKSQHQTKEEQSQITSQVTGQIGWRREGIKYRRNELFLDVLES
  VNLLMSPQGQVLSAHVSGRVVMKSYLSGMPECKFGMNDKIVIEKQGKGTADETSKSGKQS
  IAIDDCTFHQCVRLSKFDSERSISFIPPDGEFELMRYRTTKDIILPFRVIPLVREVGRTK
  LEVKVVIKSNFKPSLLAQKIEVRIPTPLNTSGVQVICMKGKAKYKASENAIVWKIKRMAG
  MKESQISAEIELLPTNDKKKWARPPISMNFEVPFAPSGLKVRYLKVFEPKLNYSDHDVIK
  WVRYIGRSGIYETRC
• 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 mu subunit binds to transmembrane cargo proteins; it recognizes the Y-X-X-Phi motifs. The surface region interacting with to the Y-X-X-Phi motif is inaccessible in cytosolic AP-2, but becomes accessible through a conformational change following phosphorylation of AP-2 mu subunit at Thr-156 in membrane-associated AP-2. The membrane-specific phosphorylation event appears to involve assembled clathrin which activates the AP-2 mu kinase AAK1. Plays a role in endocytosis of frizzled family members upon Wnt signaling.
• 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:
  Nef Mediated CD4 Down-regulation (R-HSA-167590)
  Retrograde neurotrophin signalling (R-HSA-177504)
  Nef Mediated CD8 Down-regulation (R-HSA-182218)
  Gap junction degradation (R-HSA-190873)
  Formation of annular gap junctions (R-HSA-196025)
  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 downregulation of CD28 cell surface expression (R-HSA-164939)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Epilepsy	DISBB28L	Strong	Genetic Variation	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Influenza	DIS3PNU3	Strong	Biomarker	[3]
Intellectual developmental disorder 60 with seizures	DISCBB5W	Strong	Autosomal dominant	[2]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[4]
Meningococcal disease	DISGDM2Z	Strong	Biomarker	[3]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[4]
Myoclonic-astatic epilepsy	DISTAVMU	Supportive	Unknown	[2]

11 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 AP-2 complex subunit mu (AP2M1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of AP-2 complex subunit mu (AP2M1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP-2 complex subunit mu (AP2M1).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of AP-2 complex subunit mu (AP2M1).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of AP-2 complex subunit mu (AP2M1).	[9]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of AP-2 complex subunit mu (AP2M1).	[10]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of AP-2 complex subunit mu (AP2M1).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of AP-2 complex subunit mu (AP2M1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of AP-2 complex subunit mu (AP2M1).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of AP-2 complex subunit mu (AP2M1).	[16]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of AP-2 complex subunit mu (AP2M1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of AP-2 complex subunit mu (AP2M1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of AP-2 complex subunit mu (AP2M1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of AP-2 complex subunit mu (AP2M1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of AP-2 complex subunit mu (AP2M1).	[14]

References

• [1] The AP2M1 gene expression is a promising biomarker for predicting survival of patients with hepatocellular carcinoma.J Cell Biochem. 2019 Mar;120(3):4140-4146. doi: 10.1002/jcb.27699. Epub 2018 Sep 27.
• [2] A Recurrent Missense Variant in AP2M1 Impairs Clathrin-Mediated Endocytosis and Causes Developmental and Epileptic Encephalopathy. Am J Hum Genet. 2019 Jun 6;104(6):1060-1072. doi: 10.1016/j.ajhg.2019.04.001. Epub 2019 May 16.
• [3] Hereditary properdin deficiency in three families of Tunisian Jews.Acta Paediatr. 1993 Sep;82(9):744-7. doi: 10.1111/j.1651-2227.1993.tb12550.x.
• [4] Frequent overexpression of the genes FXR1, CLAPM1 and EIF4G located on amplicon 3q26-27 in squamous cell carcinoma of the lung.Int J Cancer. 2007 Jun 15;120(12):2538-44. doi: 10.1002/ijc.22585.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [11] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [17] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.