Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4LZTP9)

• DOT Name: G protein-coupled receptor kinase 6 (GRK6)
• Synonyms: EC 2.7.11.16; G protein-coupled receptor kinase GRK6
• Gene Name: GRK6
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Diabetic kidney disease
  Glioma
  Hypopharyngeal carcinoma
  Hypopharyngeal squamous cell carcinoma
  Hypopharynx cancer
  Medulloblastoma
  Parkinson disease
  Rheumatoid arthritis
  Tardive dyskinesia
  Acute myelogenous leukaemia
  Bacterial infection
  High blood pressure
  Lung adenocarcinoma
  Neoplasm
  Thyroid gland papillary carcinoma
  Congenital factor XII deficiency
  Hereditary angioedema
  Plasma cell myeloma
  Rheumatic disorder
• UniProt ID: GRK6_HUMAN
• PDB ID: 2ACX; 3NYN; 3NYO
• EC Number: 2.7.11.16
• Pfam ID: PF00069 ; PF00615
• Sequence:
  MELENIVANTVLLKAREGGGGNRKGKSKKWRQMLQFPHISQCEELRLSLERDYHSLCERQ
  PIGRLLFREFCATRPELSRCVAFLDGVAEYEVTPDDKRKACGRQLTQNFLSHTGPDLIPE
  VPRQLVTNCTQRLEQGPCKDLFQELTRLTHEYLSVAPFADYLDSIYFNRFLQWKWLERQP
  VTKNTFRQYRVLGKGGFGEVCACQVRATGKMYACKKLEKKRIKKRKGEAMALNEKQILEK
  VNSRFVVSLAYAYETKDALCLVLTLMNGGDLKFHIYHMGQAGFPEARAVFYAAEICCGLE
  DLHRERIVYRDLKPENILLDDHGHIRISDLGLAVHVPEGQTIKGRVGTVGYMAPEVVKNE
  RYTFSPDWWALGCLLYEMIAGQSPFQQRKKKIKREEVERLVKEVPEEYSERFSPQARSLC
  SQLLCKDPAERLGCRGGSAREVKEHPLFKKLNFKRLGAGMLEPPFKPDPQAIYCKDVLDI
  EQFSTVKGVELEPTDQDFYQKFATGSVPIPWQNEMVETECFQELNVFGLDGSVPPDLDWK
  GQPPAPPKKGLLQRLFSRQDCCGNCSDSEEELPTRL
• Function: Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro).
• Tissue Specificity: Widely expressed.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Endocytosis (hsa04144)
  Morphine addiction (hsa05032)
• Reactome Pathway: G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Diabetic kidney disease	DISJMWEY	Strong	Therapeutic	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hypopharyngeal carcinoma	DISLOSB4	Strong	Biomarker	[5]
Hypopharyngeal squamous cell carcinoma	DISDDD65	Strong	Biomarker	[5]
Hypopharynx cancer	DISW5DOZ	Strong	Biomarker	[5]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[8]
Tardive dyskinesia	DISKA5RC	Strong	Biomarker	[9]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[10]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[11]
High blood pressure	DISY2OHH	moderate	Biomarker	[12]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[13]
Neoplasm	DISZKGEW	moderate	Biomarker	[14]
Thyroid gland papillary carcinoma	DIS48YMM	Disputed	Altered Expression	[14]
Congenital factor XII deficiency	DISN4DF6	Limited	Genetic Variation	[15]
Hereditary angioedema	DIS8X53J	Limited	CausalMutation	[16]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[17]
Rheumatic disorder	DIS77ACK	Limited	Biomarker	[18]

3 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 G protein-coupled receptor kinase 6 (GRK6).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of G protein-coupled receptor kinase 6 (GRK6).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of G protein-coupled receptor kinase 6 (GRK6).	[31]

12 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 G protein-coupled receptor kinase 6 (GRK6).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G protein-coupled receptor kinase 6 (GRK6).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G protein-coupled receptor kinase 6 (GRK6).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of G protein-coupled receptor kinase 6 (GRK6).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of G protein-coupled receptor kinase 6 (GRK6).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of G protein-coupled receptor kinase 6 (GRK6).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of G protein-coupled receptor kinase 6 (GRK6).	[26]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of G protein-coupled receptor kinase 6 (GRK6).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G protein-coupled receptor kinase 6 (GRK6).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G protein-coupled receptor kinase 6 (GRK6).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of G protein-coupled receptor kinase 6 (GRK6).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of G protein-coupled receptor kinase 6 (GRK6).	[33]

References

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• [3] Renoprotective effects of berberine and its possible molecular mechanisms in combination of high-fat diet and low-dose streptozotocin-induced diabetic rats.Mol Biol Rep. 2013 Mar;40(3):2405-18. doi: 10.1007/s11033-012-2321-5. Epub 2012 Nov 30.
• [4] G protein-coupled receptor kinase 6 is overexpressed in glioma and promotes glioma cell proliferation.Oncotarget. 2017 Apr 18;8(33):54227-54235. doi: 10.18632/oncotarget.17203. eCollection 2017 Aug 15.
• [5] Aberrant GRK6 promoter methylation is associated with poor prognosis in hypopharyngeal squamous cell carcinoma.Oncol Rep. 2016 Feb;35(2):1027-33. doi: 10.3892/or.2015.4469. Epub 2015 Dec 1.
• [6] Growth factor receptor-Src-mediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration.Mol Cancer. 2013 Mar 5;12:18. doi: 10.1186/1476-4598-12-18.
• [7] Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease.Sci Transl Med. 2010 Apr 21;2(28):28ra28. doi: 10.1126/scitranslmed.3000664.
• [8] Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis.FASEB J. 1999 Apr;13(6):715-25. doi: 10.1096/fasebj.13.6.715.
• [9] Tardive dyskinesia is associated with altered putamen Akt/GSK-3 signaling in nonhuman primates.Mov Disord. 2019 May;34(5):717-726. doi: 10.1002/mds.27630. Epub 2019 Jan 24.
• [10] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [11] Role of G protein-coupled receptor kinase-6 in Escherichia coli lung infection model in mice.Physiol Genomics. 2017 Nov 1;49(11):682-689. doi: 10.1152/physiolgenomics.00066.2017. Epub 2017 Sep 22.
• [12] Secreted miR-27a Induced by Cyclic Stretch Modulates the Proliferation of Endothelial Cells in Hypertension via GRK6.Sci Rep. 2017 Jan 20;7:41058. doi: 10.1038/srep41058.
• [13] Hypermethylation of the G protein-coupled receptor kinase 6 (GRK6) promoter inhibits binding of C/EBP, and GRK6 knockdown promotes cell migration and invasion in lung adenocarcinoma cells.FEBS Open Bio. 2019 Mar 19;9(4):605-617. doi: 10.1002/2211-5463.12606. eCollection 2019 Apr.
• [14] Overexpression of G Protein-Coupled Receptor Kinase 6 (GRK6) Is Associated with Progression and Poor Prognosis of Papillary Thyroid Carcinoma.Med Sci Monit. 2018 May 28;24:3540-3548. doi: 10.12659/MSM.908176.
• [15] Factor XII Osaka: abnormal factor XII with partially defective prekallikrein cleavage activity.Thromb Haemost. 2011 Mar;105(3):473-8. doi: 10.1160/TH10-02-0123. Epub 2011 Jan 25.
• [16] Characterization of patients with angioedema without wheals: the importance of F12 gene screening.Clin Immunol. 2015 Apr;157(2):239-48. doi: 10.1016/j.clim.2015.02.013. Epub 2015 Mar 2.
• [17] Down-regulated G protein-coupled receptor kinase 6 leads to apoptosis in multiple myeloma MM1R cells.Exp Ther Med. 2018 Nov;16(5):4253-4259. doi: 10.3892/etm.2018.6722. Epub 2018 Sep 11.
• [18] Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and -arrestin 2 in inflammatory macrophages.Mol Immunol. 2019 Feb;106:12-21. doi: 10.1016/j.molimm.2018.12.016. Epub 2018 Dec 18.
• [19] 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.
• [20] 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.
• [21] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [27] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.