Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTK8MUO)

• DOT Name: Ribosomal protein S6 kinase alpha-4 (RPS6KA4)
• Synonyms: S6K-alpha-4; EC 2.7.11.1; 90 kDa ribosomal protein S6 kinase 4; Nuclear mitogen- and stress-activated protein kinase 2; Ribosomal protein kinase B; RSKB
• Gene Name: RPS6KA4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Neoplasm
  Primary biliary cholangitis
  Cervical cancer
  Cervical carcinoma
  Rheumatoid arthritis
  Squamous cell carcinoma
• UniProt ID: KS6A4_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069 ; PF00433
• Sequence:
  MGDEDDDESCAVELRITEANLTGHEEKVSVENFELLKVLGTGAYGKVFLVRKAGGHDAGK
  LYAMKVLRKAALVQRAKTQEHTRTERSVLELVRQAPFLVTLHYAFQTDAKLHLILDYVSG
  GEMFTHLYQRQYFKEAEVRVYGGEIVLALEHLHKLGIIYRDLKLENVLLDSEGHIVLTDF
  GLSKEFLTEEKERTFSFCGTIEYMAPEIIRSKTGHGKAVDWWSLGILLFELLTGASPFTL
  EGERNTQAEVSRRILKCSPPFPPRIGPVAQDLLQRLLCKDPKKRLGAGPQGAQEVRNHPF
  FQGLDWVALAARKIPAPFRPQIRSELDVGNFAEEFTRLEPVYSPPGSPPPGDPRIFQGYS
  FVAPSILFDHNNAVMTDGLEAPGAGDRPGRAAVARSAMMQDSPFFQQYELDLREPALGQG
  SFSVCRRCRQRQSGQEFAVKILSRRLEANTQREVAALRLCQSHPNVVNLHEVHHDQLHTY
  LVLELLRGGELLEHIRKKRHFSESEASQILRSLVSAVSFMHEEAGVVHRDLKPENILYAD
  DTPGAPVKIIDFGFARLRPQSPGVPMQTPCFTLQYAAPELLAQQGYDESCDLWSLGVILY
  MMLSGQVPFQGASGQGGQSQAAEIMCKIREGRFSLDGEAWQGVSEEAKELVRGLLTVDPA
  KRLKLEGLRGSSWLQDGSARSSPPLRTPDVLESSGPAVRSGLNATFMAFNRGKREGFFLK
  SVENAPLAKRRKQKLRSATASRRGSPAPANPGRAPVASKGAPRRANGPLPPS
• Function: Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  TNF sig.ling pathway (hsa04668)
• Reactome Pathway: Recycling pathway of L1 (R-HSA-437239)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[3]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[4]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[10]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ribosomal protein S6 kinase alpha-4 (RPS6KA4).	[14]

References

• [1] High nuclear MSK1 is associated with longer survival in breast cancer patients.J Cancer Res Clin Oncol. 2018 Mar;144(3):509-517. doi: 10.1007/s00432-018-2579-7. Epub 2018 Jan 11.
• [2] MSK2 promotes proliferation and tumor formation in squamous cervical cancer via PAX8/RB-E2F1/cyclin A2 axis.J Cell Biochem. 2019 Jul;120(7):11432-11440. doi: 10.1002/jcb.28421. Epub 2019 Feb 12.
• [3] Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis.Nat Genet. 2011 Mar 13;43(4):329-32. doi: 10.1038/ng.789.
• [4] Gene expression profiles in squamous cell cervical carcinoma using array-based comparative genomic hybridization analysis.Int J Gynecol Cancer. 2007 May-Jun;17(3):687-96. doi: 10.1111/j.1525-1438.2007.00834.x.
• [5] Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes.Biochem Pharmacol. 2014 Jul 1;90(1):62-72. doi: 10.1016/j.bcp.2014.04.012. Epub 2014 Apr 30.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [7] 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.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [11] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] 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.
• [15] 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.