General Information of Drug Off-Target (DOT) (ID: OTQ7YKK5)

DOT Name Serine/threonine-protein kinase greatwall (MASTL)
Synonyms GW; GWL; hGWL; EC 2.7.11.1; Microtubule-associated serine/threonine-protein kinase-like; MAST-L
Gene Name MASTL
Related Disease
Estrogen-receptor positive breast cancer ( )
Breast cancer ( )
Breast carcinoma ( )
Colon cancer ( )
Colon carcinoma ( )
Colorectal carcinoma ( )
Gray platelet syndrome ( )
Hepatocellular carcinoma ( )
Non-small-cell lung cancer ( )
Thrombocytopenia ( )
Thyroid cancer ( )
Thyroid gland carcinoma ( )
Thyroid tumor ( )
Advanced cancer ( )
Carcinoma of liver and intrahepatic biliary tract ( )
Gastric cancer ( )
Liver cancer ( )
Stomach cancer ( )
Obsolete autosomal thrombocytopenia with normal platelets ( )
Neoplasm ( )
Neuroblastoma ( )
Thrombocytopenia 2 ( )
UniProt ID
GWL_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
5LOH
EC Number
2.7.11.1
Pfam ID
PF00069
Sequence
MDPTAGSKKEPGGGAATEEGVNRIAVPKPPSIEEFSIVKPISRGAFGKVYLGQKGGKLYA
VKVVKKADMINKNMTHQVQAERDALALSKSPFIVHLYYSLQSANNVYLVMEYLIGGDVKS
LLHIYGYFDEEMAVKYISEVALALDYLHRHGIIHRDLKPDNMLISNEGHIKLTDFGLSKV
TLNRDINMMDILTTPSMAKPRQDYSRTPGQVLSLISSLGFNTPIAEKNQDPANILSACLS
ETSQLSQGLVCPMSVDQKDTTPYSSKLLKSCLETVASNPGMPVKCLTSNLLQSRKRLATS
SASSQSHTFISSVESECHSSPKWEKDCQESDEALGPTMMSWNAVEKLCAKSANAIETKGF
NKKDLELALSPIHNSSALPTTGRSCVNLAKKCFSGEVSWEAVELDVNNINMDTDTSQLGF
HQSNQWAVDSGGISEEHLGKRSLKRNFELVDSSPCKKIIQNKKTCVEYKHNEMTNCYTNQ
NTGLTVEVQDLKLSVHKSQQNDCANKENIVNSFTDKQQTPEKLPIPMIAKNLMCELDEDC
EKNSKRDYLSSSFLCSDDDRASKNISMNSDSSFPGISIMESPLESQPLDSDRSIKESSFE
ESNIEDPLIVTPDCQEKTSPKGVENPAVQESNQKMLGPPLEVLKTLASKRNAVAFRSFNS
HINASNNSEPSRMNMTSLDAMDISCAYSGSYPMAITPTQKRRSCMPHQQTPNQIKSGTPY
RTPKSVRRGVAPVDDGRILGTPDYLAPELLLGRAHGPAVDWWALGVCLFEFLTGIPPFND
ETPQQVFQNILKRDIPWPEGEEKLSDNAQSAVEILLTIDDTKRAGMKELKRHPLFSDVDW
ENLQHQTMPFIPQPDDETDTSYFEARNTAQHLTVSGFSL
Function
Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.
Reactome Pathway
MASTL Facilitates Mitotic Progression (R-HSA-2465910 )

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Estrogen-receptor positive breast cancer DIS1H502 Definitive Altered Expression [1]
Breast cancer DIS7DPX1 Strong Altered Expression [2]
Breast carcinoma DIS2UE88 Strong Altered Expression [2]
Colon cancer DISVC52G Strong Altered Expression [3]
Colon carcinoma DISJYKUO Strong Altered Expression [3]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [3]
Gray platelet syndrome DISLOTCW Strong Genetic Variation [4]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [5]
Non-small-cell lung cancer DIS5Y6R9 Strong Altered Expression [6]
Thrombocytopenia DISU61YW Strong Genetic Variation [7]
Thyroid cancer DIS3VLDH Strong Biomarker [8]
Thyroid gland carcinoma DISMNGZ0 Strong Biomarker [8]
Thyroid tumor DISLVKMD Strong Biomarker [8]
Advanced cancer DISAT1Z9 moderate Altered Expression [9]
Carcinoma of liver and intrahepatic biliary tract DIS8WA0W moderate Altered Expression [10]
Gastric cancer DISXGOUK moderate Altered Expression [11]
Liver cancer DISDE4BI moderate Altered Expression [10]
Stomach cancer DISKIJSX moderate Altered Expression [11]
Obsolete autosomal thrombocytopenia with normal platelets DISHFIE8 Supportive Autosomal dominant [12]
Neoplasm DISZKGEW Limited Altered Expression [3]
Neuroblastoma DISVZBI4 Limited Biomarker [13]
Thrombocytopenia 2 DISBLVLV Limited Genetic Variation [7]
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⏷ Show the Full List of 22 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
18 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [14]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [15]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [16]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [17]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [18]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [19]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [20]
Quercetin DM3NC4M Approved Quercetin increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [22]
Cannabidiol DM0659E Approved Cannabidiol increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [23]
Troglitazone DM3VFPD Approved Troglitazone decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [24]
Azathioprine DMMZSXQ Approved Azathioprine decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [25]
Dasatinib DMJV2EK Approved Dasatinib decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [26]
Genistein DM0JETC Phase 2/3 Genistein increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [20]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [28]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [30]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [31]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of Serine/threonine-protein kinase greatwall (MASTL). [32]
OXYQUINOLINE DMZVS9Y Investigative OXYQUINOLINE decreases the expression of Serine/threonine-protein kinase greatwall (MASTL). [22]
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⏷ Show the Full List of 18 Drug(s)
4 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic increases the methylation of Serine/threonine-protein kinase greatwall (MASTL). [21]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of Serine/threonine-protein kinase greatwall (MASTL). [27]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein kinase greatwall (MASTL). [29]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of Serine/threonine-protein kinase greatwall (MASTL). [29]
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References

1 MASTL is a potential poor prognostic indicator in ER+ breast cancer.Eur Rev Med Pharmacol Sci. 2017 May;21(10):2413-2420.
2 Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer.Cell Death Differ. 2018 May;25(5):828-840. doi: 10.1038/s41418-017-0024-0. Epub 2017 Dec 11.
3 MASTL induces Colon Cancer progression and Chemoresistance by promoting Wnt/-catenin signaling.Mol Cancer. 2018 Aug 1;17(1):111. doi: 10.1186/s12943-018-0848-3.
4 Thrombocytopenias due to gray platelet syndrome or THC2 mutations.Semin Thromb Hemost. 2011 Sep;37(6):690-7. doi: 10.1055/s-0031-1291379. Epub 2011 Nov 18.
5 Inflammatory cytokine-induced expression of MASTL is involved in hepatocarcinogenesis by regulating cell cycle progression.Oncol Lett. 2019 Mar;17(3):3163-3172. doi: 10.3892/ol.2019.9983. Epub 2019 Jan 29.
6 Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC.Mol Cancer Ther. 2015 Jun;14(6):1434-44. doi: 10.1158/1535-7163.MCT-14-0846. Epub 2015 Mar 25.
7 Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets.J Clin Invest. 2018 Dec 3;128(12):5351-5367. doi: 10.1172/JCI121876. Epub 2018 Oct 29.
8 Mitosis perturbation by MASTL depletion impairs the viability of thyroid tumor cells.Cancer Lett. 2019 Feb 1;442:362-372. doi: 10.1016/j.canlet.2018.11.010. Epub 2018 Nov 14.
9 The Oncogenic Functions of MASTL Kinase.Front Cell Dev Biol. 2018 Nov 23;6:162. doi: 10.3389/fcell.2018.00162. eCollection 2018.
10 ENSA expression correlates with attenuated tumor propagation in liver cancer.Biochem Biophys Res Commun. 2013 Dec 6;442(1-2):56-61. doi: 10.1016/j.bbrc.2013.10.165. Epub 2013 Nov 8.
11 Mastl overexpression is associated with epithelial to mesenchymal transition and predicts a poor clinical outcome in gastric cancer.Oncol Lett. 2017 Dec;14(6):7283-7287. doi: 10.3892/ol.2017.7155. Epub 2017 Oct 10.
12 FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered. 2003;55(1):66-70. doi: 10.1159/000071812.
13 Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma.Cancer Lett. 2016 Feb 1;371(1):79-89. doi: 10.1016/j.canlet.2015.11.025. Epub 2015 Nov 23.
14 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
15 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.
16 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.
17 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.
18 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
19 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
20 Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
21 Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
22 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
23 Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
24 Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
25 A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
26 Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
27 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.
28 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.
29 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.
30 Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
31 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
32 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.