Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJK79EK)

• DOT Name: G protein-coupled receptor kinase 5 (GRK5)
• Synonyms: EC 2.7.11.16; G protein-coupled receptor kinase GRK5
• Gene Name: GRK5
• UniProt ID: GRK5_HUMAN
• PDB ID: 4TNB; 4TND; 6PJX
• EC Number: 2.7.11.16
• Pfam ID: PF00069 ; PF00615
• Sequence:
  MELENIVANTVLLKAREGGGGKRKGKSKKWKEILKFPHISQCEDLRRTIDRDYCSLCDKQ
  PIGRLLFRQFCETRPGLECYIQFLDSVAEYEVTPDEKLGEKGKEIMTKYLTPKSPVFIAQ
  VGQDLVSQTEEKLLQKPCKELFSACAQSVHEYLRGEPFHEYLDSMFFDRFLQWKWLERQP
  VTKNTFRQYRVLGKGGFGEVCACQVRATGKMYACKRLEKKRIKKRKGESMALNEKQILEK
  VNSQFVVNLAYAYETKDALCLVLTIMNGGDLKFHIYNMGNPGFEEERALFYAAEILCGLE
  DLHRENTVYRDLKPENILLDDYGHIRISDLGLAVKIPEGDLIRGRVGTVGYMAPEVLNNQ
  RYGLSPDYWGLGCLIYEMIEGQSPFRGRKEKVKREEVDRRVLETEEVYSHKFSEEAKSIC
  KMLLTKDAKQRLGCQEEGAAEVKRHPFFRNMNFKRLEAGMLDPPFVPDPRAVYCKDVLDI
  EQFSTVKGVNLDHTDDDFYSKFSTGSVSIPWQNEMIETECFKELNVFGPNGTLPPDLNRN
  HPPEPPKKGLLQRLFKRQHQNNSKSSPSSKTSFNHHINSNHVSSNSTGSS
• Function: Serine/threonine kinase that phosphorylates preferentially the activated forms of a variety of G-protein-coupled receptors (GPCRs). Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their down-regulation. Phosphorylates a variety of GPCRs, including adrenergic receptors, muscarinic acetylcholine receptors (more specifically Gi-coupled M2/M4 subtypes), dopamine receptors and opioid receptors. In addition to GPCRs, also phosphorylates various substrates: Hsc70-interacting protein/ST13, TP53/p53, HDAC5, and arrestin-1/ARRB1. Phosphorylation of ARRB1 by GRK5 inhibits G-protein independent MAPK1/MAPK3 signaling downstream of 5HT4-receptors. Phosphorylation of HDAC5, a repressor of myocyte enhancer factor 2 (MEF2) leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription. Phosphorylation of TP53/p53, a crucial tumor suppressor, inhibits TP53/p53-mediated apoptosis. Phosphorylation of ST13 regulates internalization of the chemokine receptor. Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor, LRP6 during Wnt signaling (in vitro).
• Tissue Specificity: Highest levels in heart, placenta, lung > skeletal muscle > brain, liver, pancreas > kidney.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Endocytosis (hsa04144)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

22 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 G protein-coupled receptor kinase 5 (GRK5).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of G protein-coupled receptor kinase 5 (GRK5).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of G protein-coupled receptor kinase 5 (GRK5).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of G protein-coupled receptor kinase 5 (GRK5).	[8]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[14]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[15]
Gamolenic acid	DMQN30Z	Approved	Gamolenic acid increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[16]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of G protein-coupled receptor kinase 5 (GRK5).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of G protein-coupled receptor kinase 5 (GRK5).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of G protein-coupled receptor kinase 5 (GRK5).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of G protein-coupled receptor kinase 5 (GRK5).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of G protein-coupled receptor kinase 5 (GRK5).	[22]

References

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• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] 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.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [15] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [16] Antineoplastic effects of gamma linolenic Acid on hepatocellular carcinoma cell lines. J Clin Biochem Nutr. 2010 Jul;47(1):81-90.
• [17] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.