Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA0SJBG)

• DOT Name: G-protein-signaling modulator 1 (GPSM1)
• Synonyms: Activator of G-protein signaling 3
• Gene Name: GPSM1
• Related Disease:
  Bacteremia
  Ankylosing spondylitis
  Episodic kinesigenic dyskinesia 1
  Esophageal squamous cell carcinoma
  Gastric cancer
  Neoplasm
  Non-insulin dependent diabetes
  Plasma cell myeloma
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Cocaine addiction
• UniProt ID: GPSM1_HUMAN
• Pfam ID: PF02188 ; PF13424
• Sequence:
  MAGPAPPVADELPGPAARRLYSRMEASCLELALEGERLCKAGDFKTGVAFFEAAVQVGTE
  DLKTLSAIYSQLGNAYFYLKEHGRALEYHKHDLLLARTIGDRMGEAKASGNLGNTLKVLG
  RFDEAAVCCQRHLSIAQEQGDKVGEARALYNIGNVYHAKGKQLSWNAANATQDPGHLPPD
  VRETLCKASEFYERNLSLVKELGDRAAQGRAYGNLGNTHYLLGNFTEATTFHKERLAIAK
  EFGDKAAERRAYSNLGNAHVFLGRFDVAAEYYKKTLQLSRQLRDQAVEAQACYSLGNTYT
  LLQDYERAAEYHLRHLLIAQELADRVGEGRACWSLGNAYVSMGRPAQALTFAKKHLQISQ
  EIGDRHGELTARMNVAQLQLVLGRLTSPAASEKPDLAGYEAQGARPKRTQRLSAETWDLL
  RLPLEREQNGDSHHSGDWRGPSRDSLPLPVRSRKYQEGPDAERRPREGSHSPLDSADVRV
  HVPRTSIPRAPSSDEECFFDLLTKFQSSRMDDQRCPLDDGQAGAAEATAAPTLEDRIAQP
  SMTASPQTEEFFDLIASSQSRRLDDQRASVGSLPGLRITHSNAGHLRGHGEPQEPGDDFF
  NMLIKYQSSRIDDQRCPPPDVLPRGPTMPDEDFFSLIQRVQAKRMDEQRVDLAGGPEQGA
  GGPPEPQQQCQPGAS
• Function: Guanine nucleotide dissociation inhibitor (GDI) which functions as a receptor-independent activator of heterotrimeric G-protein signaling. Keeps G(i/o) alpha subunit in its GDP-bound form thus uncoupling heterotrimeric G-proteins signaling from G protein-coupled receptors. Controls spindle orientation and asymmetric cell fate of cerebral cortical progenitors. May also be involved in macroautophagy in intestinal cells. May play a role in drug addiction.
• Tissue Specificity: Expressed in intestinal cells.
• KEGG Pathway: Cocaine addiction (hsa05030)
• Reactome Pathway: G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Genetic Variation	[1]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[2]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[8]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[6]
Prostate cancer	DISF190Y	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[6]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[9]

2 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-signaling modulator 1 (GPSM1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of G-protein-signaling modulator 1 (GPSM1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G-protein-signaling modulator 1 (GPSM1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G-protein-signaling modulator 1 (GPSM1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of G-protein-signaling modulator 1 (GPSM1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of G-protein-signaling modulator 1 (GPSM1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of G-protein-signaling modulator 1 (GPSM1).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of G-protein-signaling modulator 1 (GPSM1).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of G-protein-signaling modulator 1 (GPSM1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of G-protein-signaling modulator 1 (GPSM1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of G-protein-signaling modulator 1 (GPSM1).	[19]

References

• [1] Clinical characteristics and outcomes of bacteremia due to different genomic species of Acinetobacter baumannii complex in patients with solid tumors.Infection. 2012 Feb;40(1):19-26. doi: 10.1007/s15010-011-0187-4. Epub 2011 Sep 2.
• [2] Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci.Nat Genet. 2013 Jul;45(7):730-8. doi: 10.1038/ng.2667. Epub 2013 Jun 9.
• [3] Activator of G protein signaling 3 promotes epithelial cell proliferation in PKD.J Am Soc Nephrol. 2010 Aug;21(8):1275-80. doi: 10.1681/ASN.2009121224. Epub 2010 May 20.
• [4] Overexpression of activator of G-protein signaling 3 decreases the proliferation of esophageal squamous cell carcinoma.Pathol Res Pract. 2015 Jun;211(6):449-55. doi: 10.1016/j.prp.2014.12.016. Epub 2015 Feb 19.
• [5] Cyclooxygenase-2 mediated regulation of E-cadherin occurs in conventional but not early-onset gastric cancer cell lines.Cell Oncol. 2009;31(6):475-85. doi: 10.3233/CLO-2009-0496.
• [6] Activator of G protein signaling 3 modulates prostate tumor development and progression.Carcinogenesis. 2019 Dec 31;40(12):1504-1513. doi: 10.1093/carcin/bgz076.
• [7] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [8] A role for activator of G-protein signaling 3 (AGS3) in multiple myeloma.Int J Hematol. 2014 Jan;99(1):57-68. doi: 10.1007/s12185-013-1484-8. Epub 2013 Dec 5.
• [9] Activator of G protein signaling 3: a gatekeeper of cocaine sensitization and drug seeking.Neuron. 2004 Apr 22;42(2):269-81. doi: 10.1016/s0896-6273(04)00159-x.
• [10] 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.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [16] 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.
• [17] 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.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.