Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK9B9QT)

• DOT Name: AP2-associated protein kinase 1 (AAK1)
• Synonyms: EC 2.7.11.1; Adaptor-associated kinase 1
• Gene Name: AAK1
• UniProt ID: AAK1_HUMAN
• PDB ID: 4WSQ; 5L4Q; 5TE0; 8GMC; 8GMD
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MKKFFDSRREQGGSGLGSGSSGGGGSTSGLGSGYIGRVFGIGRQQVTVDEVLAEGGFAIV
  FLVRTSNGMKCALKRMFVNNEHDLQVCKREIQIMRDLSGHKNIVGYIDSSINNVSSGDVW
  EVLILMDFCRGGQVVNLMNQRLQTGFTENEVLQIFCDTCEAVARLHQCKTPIIHRDLKVE
  NILLHDRGHYVLCDFGSATNKFQNPQTEGVNAVEDEIKKYTTLSYRAPEMVNLYSGKIIT
  TKADIWALGCLLYKLCYFTLPFGESQVAICDGNFTIPDNSRYSQDMHCLIRYMLEPDPDK
  RPDIYQVSYFSFKLLKKECPIPNVQNSPIPAKLPEPVKASEAAAKKTQPKARLTDPIPTT
  ETSIAPRQRPKAGQTQPNPGILPIQPALTPRKRATVQPPPQAAGSSNQPGLLASVPQPKP
  QAPPSQPLPQTQAKQPQAPPTPQQTPSTQAQGLPAQAQATPQHQQQLFLKQQQQQQQPPP
  AQQQPAGTFYQQQQAQTQQFQAVHPATQKPAIAQFPVVSQGGSQQQLMQNFYQQQQQQQQ
  QQQQQQLATALHQQQLMTQQAALQQKPTMAAGQQPQPQPAAAPQPAPAQEPAIQAPVRQQ
  PKVQTTPPPAVQGQKVGSLTPPSSPKTQRAGHRRILSDVTHSAVFGVPASKSTQLLQAAA
  AEASLNKSKSATTTPSGSPRTSQQNVYNPSEGSTWNPFDDDNFSKLTAEELLNKDFAKLG
  EGKHPEKLGGSAESLIPGFQSTQGDAFATTSFSAGTAEKRKGGQTVDSGLPLLSVSDPFI
  PLQVPDAPEKLIEGLKSPDTSLLLPDLLPMTDPFGSTSDAVIEKADVAVESLIPGLEPPV
  PQRLPSQTESVTSNRTDSLTGEDSLLDCSLLSNPTTDLLEEFAPTAISAPVHKAAEDSNL
  ISGFDVPEGSDKVAEDEFDPIPVLITKNPQGGHSRNSSGSSESSLPNLARSLLLVDQLID
  L
• Function: Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Preferentially, may phosphorylate substrates on threonine residues. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity ; (Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue.
• Tissue Specificity: Detected in brain, heart and liver. Isoform 1 is the predominant isoform in brain.
• Reactome Pathway:
  Clathrin-mediated endocytosis (R-HSA-8856828)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)

Molecular Interaction Atlas (MIA) of This DOT

15 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 AP2-associated protein kinase 1 (AAK1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of AP2-associated protein kinase 1 (AAK1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of AP2-associated protein kinase 1 (AAK1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of AP2-associated protein kinase 1 (AAK1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of AP2-associated protein kinase 1 (AAK1).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of AP2-associated protein kinase 1 (AAK1).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of AP2-associated protein kinase 1 (AAK1).	[7]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of AP2-associated protein kinase 1 (AAK1).	[8]
Baricitinib	DM4ONW5	Approved	Baricitinib decreases the activity of AP2-associated protein kinase 1 (AAK1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of AP2-associated protein kinase 1 (AAK1).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of AP2-associated protein kinase 1 (AAK1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of AP2-associated protein kinase 1 (AAK1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of AP2-associated protein kinase 1 (AAK1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of AP2-associated protein kinase 1 (AAK1).	[16]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of AP2-associated protein kinase 1 (AAK1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of AP2-associated protein kinase 1 (AAK1).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of AP2-associated protein kinase 1 (AAK1).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of AP2-associated protein kinase 1 (AAK1).	[13]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [9] COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020 Apr;20(4):400-402. doi: 10.1016/S1473-3099(20)30132-8. Epub 2020 Feb 27.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.