Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYN79AG)

• DOT Name: Regulator of G-protein signaling 14 (RGS14)
• Synonyms: RGS14
• Gene Name: RGS14
• Related Disease:
  Chronic renal failure
  Chronic kidney disease
  Multiple sclerosis
  Obesity
  Crohn disease
  Urolithiasis
  Inflammatory bowel disease
  Neuroblastoma
  Ulcerative colitis
• UniProt ID: RGS14_HUMAN
• PDB ID: 2JNU; 2OM2; 2XNS; 3ONW; 3QI2
• Pfam ID: PF02188 ; PF02196 ; PF00615
• Sequence:
  MPGKPKHLGVPNGRMVLAVSDGELSSTTGPQGQGEGRGSSLSIHSLPSGPSSPFPTEEQP
  VASWALSFERLLQDPLGLAYFTEFLKKEFSAENVTFWKACERFQQIPASDTQQLAQEARN
  IYQEFLSSQALSPVNIDRQAWLGEEVLAEPRPDMFRAQQLQIFNLMKFDSYARFVKSPLY
  RECLLAEAEGRPLREPGSSRLGSPDATRKKPKLKPGKSLPLGVEELGQLPPVEGPGGRPL
  RKSFRRELGGTANAALRRESQGSLNSSASLDLGFLAFVSSKSESHRKSLGSTEGESESRP
  GKYCCVYLPDGTASLALARPGLTIRDMLAGICEKRGLSLPDIKVYLVGNEQALVLDQDCT
  VLADQEVRLENRITFELELTALERVVRISAKPTKRLQEALQPILEKHGLSPLEVVLHRPG
  EKQPLDLGKLVSSVAAQRLVLDTLPGVKISKARDKSPCRSQGCPPRTQDKATHPPPASPS
  SLVKVPSSATGKRQTCDIEGLVELLNRVQSSGAHDQRGLLRKEDLVLPEFLQLPAQGPSS
  EETPPQTKSAAQPIGGSLNSTTDSAL
• Function: Regulates G protein-coupled receptor signaling cascades. Inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. Besides, modulates signal transduction via G protein alpha subunits by functioning as a GDP-dissociation inhibitor (GDI). Has GDI activity on G(i) alpha subunits GNAI1 and GNAI3, but not on GNAI2 and G(o)-alpha subunit GNAO1. Has GAP activity on GNAI0, GNAI2 and GNAI3. May act as a scaffold integrating G protein and Ras/Raf MAPkinase signaling pathways. Inhibits platelet-derived growth factor (PDGF)-stimulated ERK1/ERK2 phosphorylation; a process depending on its interaction with HRAS and that is reversed by G(i) alpha subunit GNAI1. Acts as a positive modulator of microtubule polymerisation and spindle organization through a G(i)-alpha-dependent mechanism. Plays a role in cell division. Required for the nerve growth factor (NGF)-mediated neurite outgrowth. Involved in stress resistance. May be involved in visual memory processing capacity and hippocampal-based learning and memory.
• KEGG Pathway: Rap1 sig.ling pathway (hsa04015)
• Reactome Pathway: G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[1]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[2]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[4]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[5]
Urolithiasis	DISNFTKT	moderate	Genetic Variation	[6]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[7]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[8]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Regulator of G-protein signaling 14 (RGS14).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Regulator of G-protein signaling 14 (RGS14).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Regulator of G-protein signaling 14 (RGS14).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Regulator of G-protein signaling 14 (RGS14).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Regulator of G-protein signaling 14 (RGS14).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Regulator of G-protein signaling 14 (RGS14).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Regulator of G-protein signaling 14 (RGS14).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Regulator of G-protein signaling 14 (RGS14).	[16]

References

• [1] A catalog of genetic loci associated with kidney function from analyses of a million individuals.Nat Genet. 2019 Jun;51(6):957-972. doi: 10.1038/s41588-019-0407-x. Epub 2019 May 31.
• [2] Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.Am J Hum Genet. 2016 Sep 1;99(3):636-646. doi: 10.1016/j.ajhg.2016.07.012.
• [3] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [4] Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14.Aging Cell. 2018 Aug;17(4):e12751. doi: 10.1111/acel.12751. Epub 2018 Apr 14.
• [5] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [6] Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.J Am Soc Nephrol. 2019 May;30(5):855-864. doi: 10.1681/ASN.2018090942. Epub 2019 Apr 11.
• [7] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [8] Endogenous RGS14 is a cytoplasmic-nuclear shuttling protein that localizes to juxtanuclear membranes and chromatin-rich regions of the nucleus.PLoS One. 2017 Sep 21;12(9):e0184497. doi: 10.1371/journal.pone.0184497. eCollection 2017.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] 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.
• [16] 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.