Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9S73XD)

• DOT Name: MAP/microtubule affinity-regulating kinase 3 (MARK3)
• Synonyms: EC 2.7.11.1; C-TAK1; cTAK1; Cdc25C-associated protein kinase 1; ELKL motif kinase 2; EMK-2; Protein kinase STK10; Ser/Thr protein kinase PAR-1; Par-1a; Serine/threonine-protein kinase p78
• Gene Name: MARK3
• Related Disease: Visual impairment and progressive phthisis bulbi
• UniProt ID: MARK3_HUMAN
• PDB ID: 2QNJ; 3FE3; 7P1L
• EC Number: 2.7.11.1
• Pfam ID: PF02149 ; PF00069 ; PF00627
• Sequence:
  MSTRTPLPTVNERDTENHTSHGDGRQEVTSRTSRSGARCRNSIASCADEQPHIGNYRLLK
  TIGKGNFAKVKLARHILTGREVAIKIIDKTQLNPTSLQKLFREVRIMKILNHPNIVKLFE
  VIETEKTLYLIMEYASGGEVFDYLVAHGRMKEKEARSKFRQIVSAVQYCHQKRIVHRDLK
  AENLLLDADMNIKIADFGFSNEFTVGGKLDTFCGSPPYAAPELFQGKKYDGPEVDVWSLG
  VILYTLVSGSLPFDGQNLKELRERVLRGKYRIPFYMSTDCENLLKRFLVLNPIKRGTLEQ
  IMKDRWINAGHEEDELKPFVEPELDISDQKRIDIMVGMGYSQEEIQESLSKMKYDEITAT
  YLLLGRKSSELDASDSSSSSNLSLAKVRPSSDLNNSTGQSPHHKVQRSVSSSQKQRRYSD
  HAGPAIPSVVAYPKRSQTSTADSDLKEDGISSRKSSGSAVGGKGIAPASPMLGNASNPNK
  ADIPERKKSSTVPSSNTASGGMTRRNTYVCSERTTADRHSVIQNGKENSTIPDQRTPVAS
  THSISSAATPDRIRFPRGTASRSTFHGQPRERRTATYNGPPASPSLSHEATPLSQTRSRG
  STNLFSKLTSKLTRRNMSFRFIKRLPTEYERNGRYEGSSRNVSAEQKDENKEAKPRSLRF
  TWSMKTTSSMDPGDMMREIRKVLDANNCDYEQRERFLLFCVHGDGHAENLVQWEMEVCKL
  PRLSLNGVRFKRISGTSIAFKNIASKIANELKL
• Function: Serine/threonine-protein kinase. Involved in the specific phosphorylation of microtubule-associated proteins for MAP2 and MAP4. Phosphorylates the microtubule-associated protein MAPT/TAU. Phosphorylates CDC25C on 'Ser-216'. Regulates localization and activity of some histone deacetylases by mediating phosphorylation of HDAC7, promoting subsequent interaction between HDAC7 and 14-3-3 and export from the nucleus. Regulates localization and activity of MITF by mediating its phosphorylation, promoting subsequent interaction between MITF and 14-3-3 and retention in the cytosol. Negatively regulates the Hippo signaling pathway and antagonizes the phosphorylation of LATS1. Cooperates with DLG5 to inhibit the kinase activity of STK3/MST2 toward LATS1. Phosphorylates PKP2 and KSR1.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  MAP2K and MAPK activation (R-HSA-5674135)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by high-kinase activity BRAF mutants (R-HSA-6802948)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  RAF activation (R-HSA-5673000)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Visual impairment and progressive phthisis bulbi	DISVF963	Limited	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[9]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[10]

3 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 decreases the methylation of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of MAP/microtubule affinity-regulating kinase 3 (MARK3).	[8]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] 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.
• [9] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [10] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.