Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLV7EKW)

• DOT Name: Death-associated protein kinase 3 (DAPK3)
• Synonyms: DAP kinase 3; EC 2.7.11.1; DAP-like kinase; Dlk; MYPT1 kinase; Zipper-interacting protein kinase; ZIP-kinase
• Gene Name: DAPK3
• UniProt ID: DAPK3_HUMAN
• PDB ID: 1YRP; 2J90; 3BHY; 3BQR; 5A6N; 5A6O; 5VJA
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MSTFRQEDVEDHYEMGEELGSGQFAIVRKCRQKGTGKEYAAKFIKKRRLSSSRRGVSREE
  IEREVNILREIRHPNIITLHDIFENKTDVVLILELVSGGELFDFLAEKESLTEDEATQFL
  KQILDGVHYLHSKRIAHFDLKPENIMLLDKNVPNPRIKLIDFGIAHKIEAGNEFKNIFGT
  PEFVAPEIVNYEPLGLEADMWSIGVITYILLSGASPFLGETKQETLTNISAVNYDFDEEY
  FSNTSELAKDFIRRLLVKDPKRRMTIAQSLEHSWIKAIRRRNVRGEDSGRKPERRRLKTT
  RLKEYTIKSHSSLPPNNSYADFERFSKVLEEAAAAEEGLRELQRSRRLCHEDVEALAAIY
  EEKEAWYREESDSLGQDLRRLRQELLKTEALKRQAQEEAKGALLGTSGLKRRFSRLENRY
  EALAKQVASEMRFVQDLVRALEQEKLQGVECGLR
• Function: Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation and actin cytoskeleton reorganization. Involved in the regulation of smooth muscle contraction. Regulates both type I (caspase-dependent) apoptotic and type II (caspase-independent) autophagic cell deaths signal, depending on the cellular setting. Involved in regulation of starvation-induced autophagy. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A; the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca(2+) and promote a contractile state. Phosphorylates MYL12B in non-muscle cells leading to reorganization of actin cytoskeleton. Isoform 2 can phosphorylate myosin, PPP1R12A and MYL12B. Overexpression leads to condensation of actin stress fibers into thick bundles. Involved in actin filament focal adhesion dynamics. The function in both reorganization of actin cytoskeleton and focal adhesion dissolution is modulated by RhoD. Positively regulates canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, RPL13A association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Involved in regulation of cell cycle progression and cell proliferation. May be a tumor suppressor.
• Tissue Specificity: Widely expressed. Isoform 1 and isoform 2 are expressed in the bladder smooth muscle.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Pathways in cancer (hsa05200)
  Bladder cancer (hsa05219)
• Reactome Pathway: Caspase activation via Dependence Receptors in the absence of ligand (R-HSA-418889)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Death-associated protein kinase 3 (DAPK3) affects the response to substance of Methotrexate.	[15]

13 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 Death-associated protein kinase 3 (DAPK3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Death-associated protein kinase 3 (DAPK3).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Death-associated protein kinase 3 (DAPK3).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Death-associated protein kinase 3 (DAPK3).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Death-associated protein kinase 3 (DAPK3).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Death-associated protein kinase 3 (DAPK3).	[7]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Death-associated protein kinase 3 (DAPK3).	[8]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Death-associated protein kinase 3 (DAPK3).	[9]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Death-associated protein kinase 3 (DAPK3).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Death-associated protein kinase 3 (DAPK3).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Death-associated protein kinase 3 (DAPK3).	[7]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Death-associated protein kinase 3 (DAPK3).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Death-associated protein kinase 3 (DAPK3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Death-associated protein kinase 3 (DAPK3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Death-associated protein kinase 3 (DAPK3).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Death-associated protein kinase 3 (DAPK3).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Death-associated protein kinase 3 (DAPK3).	[5]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Death-associated protein kinase 3 (DAPK3).	[5]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] DNA methyltransferase inhibitor 5-aza-CdR enhances the radiosensitivity of gastric cancer cells. Cancer Sci. 2009 Jan;100(1):181-8. doi: 10.1111/j.1349-7006.2008.01004.x. Epub 2008 Nov 25.
• [7] 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.
• [8] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [9] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [14] 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.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.