Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6Z2TGV)

• DOT Name: MAP/microtubule affinity-regulating kinase 4 (MARK4)
• Synonyms: EC 2.7.11.1; MAP/microtubule affinity-regulating kinase-like 1
• Gene Name: MARK4
• Related Disease:
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Adult glioblastoma
  Age-related macular degeneration
  Arteriosclerosis
  Atherosclerosis
  Brain neoplasm
  Breast neoplasm
  Creutzfeldt Jacob disease
  Glioblastoma multiforme
  Hyperlipidemia
  Neovascular age-related macular degeneration
  Peutz-Jeghers syndrome
  Trichohepatoenteric syndrome
  Type-1/2 diabetes
  Alzheimer disease
  Coronary heart disease
  Obesity
  Non-insulin dependent diabetes
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
  Prion disease
  Stroke
  Tauopathy
• UniProt ID: MARK4_HUMAN
• PDB ID: 5ES1
• EC Number: 2.7.11.1
• Pfam ID: PF02149 ; PF00069 ; PF00627
• Sequence:
  MSSRTVLAPGNDRNSDTHGTLGSGRSSDKGPSWSSRSLGARCRNSIASCPEEQPHVGNYR
  LLRTIGKGNFAKVKLARHILTGREVAIKIIDKTQLNPSSLQKLFREVRIMKGLNHPNIVK
  LFEVIETEKTLYLVMEYASAGEVFDYLVSHGRMKEKEARAKFRQIVSAVHYCHQKNIVHR
  DLKAENLLLDAEANIKIADFGFSNEFTLGSKLDTFCGSPPYAAPELFQGKKYDGPEVDIW
  SLGVILYTLVSGSLPFDGHNLKELRERVLRGKYRVPFYMSTDCESILRRFLVLNPAKRCT
  LEQIMKDKWINIGYEGEELKPYTEPEEDFGDTKRIEVMVGMGYTREEIKESLTSQKYNEV
  TATYLLLGRKTEEGGDRGAPGLALARVRAPSDTTNGTSSSKGTSHSKGQRSSSSTYHRQR
  RHSDFCGPSPAPLHPKRSPTSTGEAELKEERLPGRKASCSTAGSGSRGLPPSSPMVSSAH
  NPNKAEIPERRKDSTSTPNNLPPSMMTRRNTYVCTERPGAERPSLLPNGKENSSGTPRVP
  PASPSSHSLAPPSGERSRLARGSTIRSTFHGGQVRDRRAGGGGGGGVQNGPPASPTLAHE
  AAPLPAGRPRPTTNLFTKLTSKLTRRVADEPERIGGPEVTSCHLPWDQTETAPRLLRFPW
  SVKLTSSRPPEALMAALRQATAAARCRCRQPQPFLLACLHGGAGGPEPLSHFEVEVCQLP
  RPGLRGVLFRRVAGTALAFRTLVTRISNDLEL
• Function: Serine/threonine-protein kinase. Phosphorylates the microtubule-associated protein MAPT/TAU. Also phosphorylates the microtubule-associated proteins MAP2 and MAP4. Involved in regulation of the microtubule network, causing reorganization of microtubules into bundles. Required for the initiation of axoneme extension during cilium assembly. Regulates the centrosomal location of ODF2 and phosphorylates ODF2 in vitro. Plays a role in cell cycle progression, specifically in the G1/S checkpoint. Reduces neuronal cell survival. Plays a role in energy homeostasis by regulating satiety and metabolic rate. Promotes adipogenesis by activating JNK1 and inhibiting the p38MAPK pathway, and triggers apoptosis by activating the JNK1 pathway. Phosphorylates mTORC1 complex member RPTOR and acts as a negative regulator of the mTORC1 complex, probably due to disruption of the interaction between phosphorylated RPTOR and the RRAGA/RRAGC heterodimer which is required for mTORC1 activation. Involved in NLRP3 positioning along microtubules by mediating NLRP3 recruitment to microtubule organizing center (MTOC) upon inflammasome activation.
• Tissue Specificity: Ubiquitous. Isoform 2 is brain-specific . Expressed at highest levels in brain and testis. Also expressed in heart, lung, liver, muscle, kidney and spleen .
• Reactome Pathway: Anchoring of the basal body to the plasma membrane (R-HSA-5620912)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[2]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Age-related macular degeneration	DIS0XS2C	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[7]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Genetic Variation	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[9]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Genetic Variation	[5]
Peutz-Jeghers syndrome	DISF27ZJ	Strong	Genetic Variation	[10]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Altered Expression	[9]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[11]
Alzheimer disease	DISF8S70	moderate	Genetic Variation	[12]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[13]
Obesity	DIS47Y1K	moderate	Biomarker	[14]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Breast cancer	DIS7DPX1	Limited	Biomarker	[16]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[16]
Lung cancer	DISCM4YA	Limited	Altered Expression	[17]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[17]
Prion disease	DISOUMB0	Limited	Genetic Variation	[18]
Stroke	DISX6UHX	Limited	Altered Expression	[19]
Tauopathy	DISY2IPA	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	MAP/microtubule affinity-regulating kinase 4 (MARK4) decreases the response to substance of Afimoxifene.	[32]

9 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 MAP/microtubule affinity-regulating kinase 4 (MARK4).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[26]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[29]
T83193	DMHO29Y	Patented	T83193 decreases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[31]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde decreases the expression of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of MAP/microtubule affinity-regulating kinase 4 (MARK4).	[30]

References

• [1] Suggestive evidence on the involvement of polypyrimidine-tract binding protein in regulating alternative splicing of MAP/microtubule affinity-regulating kinase 4 in glioma.Cancer Lett. 2015 Apr 1;359(1):87-96. doi: 10.1016/j.canlet.2014.12.049. Epub 2015 Jan 8.
• [2] Discovery of Coumarin as Microtubule Affinity-Regulating Kinase 4 Inhibitor That Sensitize Hepatocellular Carcinoma to Paclitaxel.Front Chem. 2019 May 24;7:366. doi: 10.3389/fchem.2019.00366. eCollection 2019.
• [3] Differential signature of the centrosomal MARK4 isoforms in glioma.Anal Cell Pathol (Amst). 2011;34(6):319-38. doi: 10.3233/ACP-2011-0031.
• [4] The neural progenitor-restricted isoform of the MARK4 gene in 19q13.2 is upregulated in human gliomas and overexpressed in a subset of glioblastoma cell lines.Oncogene. 2003 May 1;22(17):2581-91. doi: 10.1038/sj.onc.1206336.
• [5] A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.
• [6] MARK4 (Microtubule Affinity-Regulating Kinase 4)-Dependent Inflammasome Activation Promotes Atherosclerosis-Brief Report.Arterioscler Thromb Vasc Biol. 2019 Aug;39(8):1645-1651. doi: 10.1161/ATVBAHA.119.312478. Epub 2019 Jun 6.
• [7] Investigation of two Wnt signalling pathway single nucleotide polymorphisms in a breast cancer-affected Australian population.Twin Res Hum Genet. 2011 Dec;14(6):562-7. doi: 10.1375/twin.14.6.562.
• [8] Reduction of protein kinase MARK4 in the brains of experimental scrapie rodents and human prion disease correlates with deposits of PrP(Sc).Int J Mol Med. 2012 Sep;30(3):569-78. doi: 10.3892/ijmm.2012.1025. Epub 2012 Jun 12.
• [9] Differential Expression of MARK4 Protein and Related Perturbations in Females with Ovulatory PCOS.Endocr Metab Immune Disord Drug Targets. 2019;19(7):1064-1074. doi: 10.2174/1871530319666190719145823.
• [10] Genetic defects underlying Peutz-Jeghers syndrome (PJS) and exclusion of the polarity-associated MARK/Par1 gene family as potential PJS candidates.Clin Genet. 2007 Dec;72(6):568-73. doi: 10.1111/j.1399-0004.2007.00907.x. Epub 2007 Oct 9.
• [11] Identification and evaluation of bioactive natural products as potential inhibitors of human microtubule affinity-regulating kinase 4 (MARK4).J Biomol Struct Dyn. 2019 Apr;37(7):1813-1829. doi: 10.1080/07391102.2018.1468282. Epub 2018 May 24.
• [12] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [13] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [14] Molecular Characterization of Microtubule Affinity-Regulating Kinase4 from Sus scrofa and Promotion of Lipogenesis in Primary Porcine Placental Trophoblasts.Int J Mol Sci. 2019 Mar 9;20(5):1206. doi: 10.3390/ijms20051206.
• [15] Evaluation of human microtubule affinity-regulating kinase 4 inhibitors: fluorescence binding studies, enzyme, and cell assays.J Biomol Struct Dyn. 2017 Nov;35(14):3194-3203. doi: 10.1080/07391102.2016.1249958. Epub 2016 Nov 3.
• [16] MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells.EMBO Rep. 2017 Mar;18(3):420-436. doi: 10.15252/embr.201642455. Epub 2017 Feb 9.
• [17] miR-515-5p controls cancer cell migration through MARK4 regulation.EMBO Rep. 2016 Apr;17(4):570-84. doi: 10.15252/embr.201540970. Epub 2016 Feb 10.
• [18] Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.Hum Mol Genet. 2012 Apr 15;21(8):1897-906. doi: 10.1093/hmg/ddr607. Epub 2011 Dec 30.
• [19] Ischemic axonal injury up-regulates MARK4 in cortical neurons and primes tau phosphorylation and aggregation.Acta Neuropathol Commun. 2019 Aug 20;7(1):135. doi: 10.1186/s40478-019-0783-6.
• [20] Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment.Sci Rep. 2016 Oct 6;6:34784. doi: 10.1038/srep34784.
• [21] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [22] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [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] 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.
• [25] 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.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] ON 01910.Na is selectively cytotoxic for chronic lymphocytic leukemia cells through a dual mechanism of action involving PI3K/AKT inhibition and induction of oxidative stress. Clin Cancer Res. 2012 Apr 1;18(7):1979-91. doi: 10.1158/1078-0432.CCR-11-2113. Epub 2012 Feb 20.
• [28] 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.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] 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.
• [31] Antimutagenicity of cinnamaldehyde and vanillin in human cells: Global gene expression and possible role of DNA damage and repair. Mutat Res. 2007 Mar 1;616(1-2):60-9. doi: 10.1016/j.mrfmmm.2006.11.022. Epub 2006 Dec 18.
• [32] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.