Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT065FSS)

• DOT Name: G protein pathway suppressor 2 (GPS2)
• Synonyms: GPS-2
• Gene Name: GPS2
• Related Disease:
  Fatty liver disease
  Gray platelet syndrome
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Non-insulin dependent diabetes
  Obesity
  Ileus
  Liposarcoma
  Small lymphocytic lymphoma
• UniProt ID: GPS2_HUMAN
• PDB ID: 2L5G
• Pfam ID: PF15991
• Sequence:
  MPALLERPKLSNAMARALHRHIMMERERKRQEEEEVDKMMEQKMKEEQERRKKKEMEERM
  SLEETKEQILKLEEKLLALQEEKHQLFLQLKKVLHEEEKRRRKEQSDLTTLTSAAYQQSL
  TVHTGTHLLSMQGSPGGHNRPGTLMAADRAKQMFGPQVLTTRHYVGSAAAFAGTPEHGQF
  QGSPGGAYGTAQPPPHYGPTQPAYSPSQQLRAPSAFPAVQYLSQPQPQPYAVHGHFQPTQ
  TGFLQPGGALSLQKQMEHANQQTGFSDSSSLRPMHPQALHPAPGLLASPQLPVQMQPAGK
  SGFAATSQPGPRLPFIQHSQNPRFYHK
• Function: Key regulator of inflammation, lipid metabolism and mitochondrion homeostasis that acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, thereby inhibiting 'Lys-63'-linked ubiquitination. In the nucleus, can both acts as a corepressor and coactivator of transcription, depending on the context. Acts as a transcription coactivator in adipocytes by promoting the recruitment of PPARG to promoters: acts by inhibiting the activity of the ubiquitin-conjugating enzyme UBE2N/Ubc13, leading to stabilization of KDM4A and subsequent histone H3 'Lys-9' (H3K9) demethylation. Promotes cholesterol efflux by acting as a transcription coactivator. Acts as a regulator of B-cell development by inhibiting UBE2N/Ubc13, thereby restricting the activation of Toll-like receptors (TLRs) and B-cell antigen receptors (BCRs) signaling pathways. Acts as a key mediator of mitochondrial stress response: in response to mitochondrial depolarization, relocates from the mitochondria to the nucleus following desumoylation and specifically promotes expression of nuclear-encoded mitochondrial genes. Promotes transcription of nuclear-encoded mitochondrial genes by inhibiting UBE2N/Ubc13. Can also act as a corepressor as part of the N-Cor repressor complex by repressing active PPARG. Plays an anti-inflammatory role in macrophages and is required for insulin sensitivity by acting as a corepressor. Plays an anti-inflammatory role during the hepatic acute phase response by interacting with sumoylated NR1H2 and NR5A2 proteins, thereby preventing N-Cor corepressor complex dissociation. In the cytosol, also plays a non-transcriptional role by regulating insulin signaling and pro-inflammatory pathways. In the cytoplasm, acts as a negative regulator of inflammation by inhibiting the pro-inflammatory TNF-alpha pathway; acts by repressing UBE2N/Ubc13 activity. In the cytoplasm of adipocytes, restricts the activation of insulin signaling via inhibition of UBE2N/Ubc13-mediated ubiquitination of AKT. Able to suppress G-protein- and mitogen-activated protein kinase-mediated signal transduction. Acts as a tumor-suppressor in liposarcoma ; (Microbial infection) Required for efficient replication of hepatitis C virus (HCV) by promoting the interaction between VAPA and HCV virus protein NS5A.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  HDACs deacetylate histones (R-HSA-3214815)
  Loss of MECP2 binding ability to the NCoR/SMRT complex (R-HSA-9022537)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  HCMV Early Events (R-HSA-9609690)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fatty liver disease	DIS485QZ	Strong	Biomarker	[1]
Gray platelet syndrome	DISLOTCW	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[1]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Altered Expression	[3]
Ileus	DISH7JW9	Limited	Biomarker	[4]
Liposarcoma	DIS8IZVM	Limited	Biomarker	[5]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[6]

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 pathway suppressor 2 (GPS2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G protein pathway suppressor 2 (GPS2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of G protein pathway suppressor 2 (GPS2).	[8]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of G protein pathway suppressor 2 (GPS2).	[9]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of G protein pathway suppressor 2 (GPS2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of G protein pathway suppressor 2 (GPS2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of G protein pathway suppressor 2 (GPS2).	[13]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal increases the expression of G protein pathway suppressor 2 (GPS2).	[14]

References

• [1] Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPAR.Nat Commun. 2019 Apr 11;10(1):1684. doi: 10.1038/s41467-019-09524-z.
• [2] Glasgow prognostic score predicts therapeutic outcome after hepatic resection for hepatocellular carcinoma.Oncol Lett. 2017 Jul;14(1):293-298. doi: 10.3892/ol.2017.6104. Epub 2017 Apr 28.
• [3] G protein pathway suppressor 2 (GPS2) links inflammation and cholesterol efflux by controlling lipopolysaccharide-induced ATP-binding cassette transporter A1 expression in macrophages.FASEB J. 2019 Feb;33(2):1631-1643. doi: 10.1096/fj.201801123R. Epub 2018 Aug 28.
• [4] A high preoperative Glasgow prognostic score predicts a high likelihood of conversion from laparoscopic to open surgery in patients with colon cancer.Surg Endosc. 2019 Apr;33(4):1111-1116. doi: 10.1007/s00464-018-6369-8. Epub 2018 Jul 25.
• [5] G protein pathway suppressor 2 (GPS2) acts as a tumor suppressor in liposarcoma.Tumour Biol. 2016 Oct;37(10):13333-13343. doi: 10.1007/s13277-016-5220-x. Epub 2016 Jul 26.
• [6] Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation.Clin Cancer Res. 2017 Feb 1;23(3):735-745. doi: 10.1158/1078-0432.CCR-16-0594. Epub 2016 Aug 8.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.