Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein kinase 3 (STK3)
• Synonyms: EC 2.7.11.1; Mammalian STE20-like protein kinase 2; MST-2; STE20-like kinase MST2; Serine/threonine-protein kinase Krs-1
• Gene Name: STK3
• Related Disease:
  Acute myelogenous leukaemia
  Autoimmune disease
  Beta thalassemia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  High blood pressure
  Isolated cleft lip
  Malaria
  Megalencephaly
  Neoplasm
  Renal cell carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Clear cell renal carcinoma
  Malignant soft tissue neoplasm
  Sarcoma
  Soft tissue sarcoma
  Advanced cancer
  Fibrosarcoma
  Melanoma
  Metastatic malignant neoplasm
• UniProt ID: STK3_HUMAN
• PDB ID: 3WWS; 4HKD; 4L0N; 4LG4; 4LGD; 4OH9; 5BRM; 5DH3; 6AO5; 6AR2; 8A66
• EC Number: 2.7.11.1
• Pfam ID: PF11629 ; PF00069
• Sequence:
  MEQPPAPKSKLKKLSEDSLTKQPEEVFDVLEKLGEGSYGSVFKAIHKESGQVVAIKQVPV
  ESDLQEIIKEISIMQQCDSPYVVKYYGSYFKNTDLWIVMEYCGAGSVSDIIRLRNKTLIE
  DEIATILKSTLKGLEYLHFMRKIHRDIKAGNILLNTEGHAKLADFGVAGQLTDTMAKRNT
  VIGTPFWMAPEVIQEIGYNCVADIWSLGITSIEMAEGKPPYADIHPMRAIFMIPTNPPPT
  FRKPELWSDDFTDFVKKCLVKNPEQRATATQLLQHPFIKNAKPVSILRDLITEAMEIKAK
  RHEEQQRELEEEEENSDEDELDSHTMVKTSVESVGTMRATSTMSEGAQTMIEHNSTMLES
  DLGTMVINSEDEEEEDGTMKRNATSPQVQRPSFMDYFDKQDFKNKSHENCNQNMHEPFPM
  SKNVFPDNWKVPQDGDFDFLKNLSLEELQMRLKALDPMMEREIEELRQRYTAKRQPILDA
  MDAKKRRQQNF
• Function: Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Key component of the Hippo signaling pathway which plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Phosphorylation of YAP1 by LATS2 inhibits its translocation into the nucleus to regulate cellular genes important for cell proliferation, cell death, and cell migration. STK3/MST2 and STK4/MST1 are required to repress proliferation of mature hepatocytes, to prevent activation of facultative adult liver stem cells (oval cells), and to inhibit tumor formation. Phosphorylates NKX2-1. Phosphorylates NEK2 and plays a role in centrosome disjunction by regulating the localization of NEK2 to centrosome, and its ability to phosphorylate CROCC and CEP250. In conjunction with SAV1, activates the transcriptional activity of ESR1 through the modulation of its phosphorylation. Positively regulates RAF1 activation via suppression of the inhibitory phosphorylation of RAF1 on 'Ser-259'. Phosphorylates MOBKL1A and RASSF2. Phosphorylates MOBKL1B on 'Thr-74'. Acts cooperatively with MOBKL1B to activate STK38.
• Tissue Specificity: Expressed at high levels in adult kidney, skeletal and placenta tissues and at very low levels in adult heart, lung and brain tissues.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway: Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Beta thalassemia	DIS5RCQK	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[8]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[9]
Malaria	DISQ9Y50	Strong	Genetic Variation	[10]
Megalencephaly	DISYW5SV	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Posttranslational Modification	[12]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[13]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[14]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[14]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[14]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[12]
Malignant soft tissue neoplasm	DISTC6NO	moderate	Biomarker	[15]
Sarcoma	DISZDG3U	moderate	Biomarker	[15]
Soft tissue sarcoma	DISSN8XB	moderate	Posttranslational Modification	[15]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[16]
Fibrosarcoma	DISWX7MU	Limited	Genetic Variation	[17]
Melanoma	DIS1RRCY	Limited	Biomarker	[17]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[18]

12 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 3 (STK3).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase 3 (STK3).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein kinase 3 (STK3).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase 3 (STK3).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein kinase 3 (STK3).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Serine/threonine-protein kinase 3 (STK3).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein kinase 3 (STK3).	[25]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Serine/threonine-protein kinase 3 (STK3).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein kinase 3 (STK3).	[30]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Serine/threonine-protein kinase 3 (STK3).	[31]
AHPN	DM8G6O4	Investigative	AHPN increases the expression of Serine/threonine-protein kinase 3 (STK3).	[32]
Ginsenoside RG3	DMFN58T	Investigative	Ginsenoside RG3 increases the expression of Serine/threonine-protein kinase 3 (STK3).	[33]

4 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 affects the methylation of Serine/threonine-protein kinase 3 (STK3).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Serine/threonine-protein kinase 3 (STK3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein kinase 3 (STK3).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Serine/threonine-protein kinase 3 (STK3).	[28]

References

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• [2] Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease.J Immunol. 2014 Feb 15;192(4):1525-35. doi: 10.4049/jimmunol.1301060. Epub 2014 Jan 22.
• [3] A beta-thalassemia lesion abolishes the same Mst II site as the sickle mutation.Nucleic Acids Res. 1983 Nov 25;11(22):7789-94. doi: 10.1093/nar/11.22.7789.
• [4] FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis.Cell Death Differ. 2019 Dec;26(12):2577-2593. doi: 10.1038/s41418-019-0321-x. Epub 2019 Mar 22.
• [5] Mammalian MST2 kinase and human Salvador activate and reduce estrogen receptor alpha in the absence of ligand.J Mol Med (Berl). 2011 Feb;89(2):181-91. doi: 10.1007/s00109-010-0698-y. Epub 2010 Nov 23.
• [6] Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance.Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):E1312-20. doi: 10.1073/pnas.1110428108. Epub 2011 Oct 31.
• [7] Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma.Gut. 2018 Sep;67(9):1692-1703. doi: 10.1136/gutjnl-2017-314061. Epub 2017 Sep 2.
• [8] Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.PLoS Genet. 2017 May 12;13(5):e1006728. doi: 10.1371/journal.pgen.1006728. eCollection 2017 May.
• [9] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [10] Negligible Impact of Mass Screening and Treatment on Mesoendemic Malaria Transmission at West Timor in Eastern Indonesia: A Cluster-Randomized Trial.Clin Infect Dis. 2018 Oct 15;67(9):1364-1372. doi: 10.1093/cid/ciy231.
• [11] A de novo mutation in the X-linked PAK3 gene is the underlying cause of intellectual disability and macrocephaly in monozygotic twins.Eur J Med Genet. 2017 Apr;60(4):212-216. doi: 10.1016/j.ejmg.2017.01.004. Epub 2017 Jan 24.
• [12] Overexpression of the YAP1 oncogene in clear cell renal cell carcinoma is associated with poor outcome.Oncol Rep. 2017 Jul;38(1):427-439. doi: 10.3892/or.2017.5642. Epub 2017 May 15.
• [13] AIF downregulation and its interaction with STK3 in renal cell carcinoma.PLoS One. 2014 Jul 3;9(7):e100824. doi: 10.1371/journal.pone.0100824. eCollection 2014.
• [14] Frequent epigenetic inactivation of RASSF2 in thyroid cancer and functional consequences.Mol Cancer. 2010 Sep 29;9:264. doi: 10.1186/1476-4598-9-264.
• [15] Frequent hypermethylation of MST1 and MST2 in soft tissue sarcoma.Mol Carcinog. 2007 Oct;46(10):865-71. doi: 10.1002/mc.20317.
• [16] Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway.Cell Commun Signal. 2018 Jul 3;16(1):37. doi: 10.1186/s12964-018-0250-1.
• [17] MAPK and Hippo signaling pathways crosstalk via the RAF-1/MST-2 interaction in malignant melanoma.Oncol Rep. 2017 Aug;38(2):1199-1205. doi: 10.3892/or.2017.5774. Epub 2017 Jun 30.
• [18] Hippo kinases regulate cell junctions to inhibit tumor metastasis in response to oxidative stress.Redox Biol. 2019 Sep;26:101233. doi: 10.1016/j.redox.2019.101233. Epub 2019 Jun 4.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [25] 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.
• [26] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [27] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [28] 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.
• [29] 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.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [32] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [33] Ginsenoside Rg3 attenuates the osimertinib resistance by reducing the stemness of non-small cell lung cancer cells. Environ Toxicol. 2020 Jun;35(6):643-651. doi: 10.1002/tox.22899. Epub 2020 Jan 9.