Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKOJ3JB)

• DOT Name: Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA)
• Synonyms: Alpha-SGT; Vpu-binding protein; UBP
• Gene Name: SGTA
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Aplasia cutis congenita
  Breast neoplasm
  Cardiac failure
  Congestive heart failure
  Corpus callosum, agenesis of
  Esophageal squamous cell carcinoma
  Lung adenocarcinoma
  Prostate neoplasm
  Visceral leishmaniasis
  Advanced cancer
  Gastric cancer
  Influenza
  Neoplasm
  Stomach cancer
  Adult glioblastoma
  Benign neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Glioblastoma multiforme
  Lewy body dementia
  Ovarian cancer
  Parkinson disease
• UniProt ID: SGTA_HUMAN
• PDB ID: 2VYI; 4CPG; 4GOD; 4GOE; 4GOF
• Pfam ID: PF16546 ; PF00515 ; PF13181
• Sequence:
  MDNKKRLAYAIIQFLHDQLRHGGLSSDAQESLEVAIQCLETAFGVTVEDSDLALPQTLPE
  IFEAAATGKEMPQDLRSPARTPPSEEDSAEAERLKTEGNEQMKVENFEAAVHFYGKAIEL
  NPANAVYFCNRAAAYSKLGNYAGAVQDCERAICIDPAYSKAYGRMGLALSSLNKHVEAVA
  YYKKALELDPDNETYKSNLKIAELKLREAPSPTGGVGSFDIAGLLNNPGFMSMASNLMNN
  PQIQQLMSGMISGGNNPLGTPGTSPSQNDLASLIQAGQQFAQQMQQQNPELIEQLRSQIR
  SRTPSASNDDQQE
• Function: Co-chaperone that binds misfolded and hydrophobic patches-containing client proteins in the cytosol. Mediates their targeting to the endoplasmic reticulum but also regulates their sorting to the proteasome when targeting fails. Functions in tail-anchored/type II transmembrane proteins membrane insertion constituting with ASNA1 and the BAG6 complex a targeting module. Functions upstream of the BAG6 complex and ASNA1, binding more rapidly the transmembrane domain of newly synthesized proteins. It is also involved in the regulation of the endoplasmic reticulum-associated misfolded protein catabolic process via its interaction with BAG6: collaborates with the BAG6 complex to maintain hydrophobic substrates in non-ubiquitinated states. Competes with RNF126 for interaction with BAG6, preventing the ubiquitination of client proteins associated with the BAG6 complex. Binds directly to HSC70 and HSP70 and regulates their ATPase activity ; (Microbial infection) In case of infection by polyomavirus, involved in the virus endoplasmic reticulum membrane penetration and infection via interaction with DNAJB12, DNAJB14 and HSPA8/Hsc70.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Protein export (hsa03060)
• Reactome Pathway: Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Aplasia cutis congenita	DISMDAYM	Strong	Genetic Variation	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Visceral leishmaniasis	DISTKEYK	Strong	Genetic Variation	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Gastric cancer	DISXGOUK	moderate	Biomarker	[8]
Influenza	DIS3PNU3	moderate	Altered Expression	[9]
Neoplasm	DISZKGEW	moderate	Biomarker	[10]
Stomach cancer	DISKIJSX	moderate	Biomarker	[8]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[10]
Benign neoplasm	DISDUXAD	Limited	Biomarker	[11]
Breast cancer	DIS7DPX1	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[12]
Carcinoma	DISH9F1N	Limited	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[10]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[13]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[11]
Parkinson disease	DISQVHKL	Limited	Altered Expression	[13]

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 Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[21]

7 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 Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small glutamine-rich tetratricopeptide repeat-containing protein alpha (SGTA).	[22]

References

• [1] Molecular cloning of canine co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein (SGTA) and investigation of its ability to suppress androgen receptor signalling in androgen-independent prostate cancer.Vet J. 2015 Nov;206(2):143-8. doi: 10.1016/j.tvjl.2015.08.002. Epub 2015 Aug 7.
• [2] Clinical, pathological and treatment factors associated with the survival of patients with primary pulmonary salivary gland-type tumors.Lung Cancer. 2018 Dec;126:174-181. doi: 10.1016/j.lungcan.2018.11.010. Epub 2018 Nov 10.
• [3] Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor.Oncoimmunology. 2018 Aug 1;7(10):e1484982. doi: 10.1080/2162402X.2018.1484982. eCollection 2018.
• [4] A systematic review of large scale and heterogeneous gene array data in heart failure.J Mol Cell Cardiol. 2005 Mar;38(3):425-32. doi: 10.1016/j.yjmcc.2004.12.016.
• [5] High expression of SGTA in esophageal squamous cell carcinoma correlates with proliferation and poor prognosis.J Cell Biochem. 2014 Jan;115(1):141-50. doi: 10.1002/jcb.24641.
• [6] Control of androgen receptor signaling in prostate cancer by the cochaperone small glutamine rich tetratricopeptide repeat containing protein alpha.Cancer Res. 2007 Oct 15;67(20):10087-96. doi: 10.1158/0008-5472.CAN-07-1646.
• [7] Recombinant small glutamine-rich tetratricopeptide repeat-containing protein of Leishmania infantum: Potential vaccine and diagnostic application against visceral leishmaniasis.Mol Immunol. 2017 Nov;91:272-281. doi: 10.1016/j.molimm.2017.09.017. Epub 2017 Oct 5.
• [8] SGT1 regulates Akt signaling by promoting beta-TrCP-dependent PHLPP1 degradation in gastric cancer cells.Mol Biol Rep. 2013 Apr;40(4):2947-53. doi: 10.1007/s11033-012-2363-8. Epub 2013 Feb 26.
• [9] Optimized Expression, Purification, and Rapid Detection of Recombinant Influenza Nucleoproteins Expressed in Sf9 Insect Cells.J Microbiol Biotechnol. 2018 Oct 28;28(10):1683-1690. doi: 10.4014/jmb.1805.05053.
• [10] A tumor-targeting nanomedicine carrying the p53 gene crosses the blood-brain barrier and enhances anti-PD-1 immunotherapy in mouse models of glioblastoma.Int J Cancer. 2019 Nov 1;145(9):2535-2546. doi: 10.1002/ijc.32531. Epub 2019 Jul 8.
• [11] Androgen receptor protein levels are significantly reduced in serous ovarian carcinomas compared with benign or borderline disease but are not altered by cancer stage or metastatic progression.Horm Cancer. 2013 Jun;4(3):154-64. doi: 10.1007/s12672-013-0135-0. Epub 2013 Feb 27.
• [12] Expression and prognostic role of SGTA in human breast carcinoma correlates with tumor cell proliferation.J Mol Histol. 2014 Dec;45(6):665-77. doi: 10.1007/s10735-014-9586-z. Epub 2014 Jul 16.
• [13] HSP90 and Its Novel Co-Chaperones, SGT1 and CHP-1, in Brain of Patients with Parkinson's Disease and Dementia with Lewy Bodies.J Parkinsons Dis. 2019;9(1):97-107. doi: 10.3233/JPD-181443.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.