Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ7YUX1)

• DOT Name: Syntaxin-4 (STX4)
• Synonyms: Renal carcinoma antigen NY-REN-31
• Gene Name: STX4
• Related Disease:
  Advanced cancer
  Hepatitis C virus infection
  Neoplasm
  Non-insulin dependent diabetes
  Plasma cell myeloma
  Prostate cancer
  Prostate neoplasm
  Type-1/2 diabetes
• UniProt ID: STX4_HUMAN
• Pfam ID: PF05739 ; PF00804
• Sequence:
  MRDRTHELRQGDDSSDEEDKERVALVVHPGTARLGSPDEEFFHKVRTIRQTIVKLGNKVQ
  ELEKQQVTILATPLPEESMKQELQNLRDEIKQLGREIRLQLKAIEPQKEEADENYNSVNT
  RMRKTQHGVLSQQFVELINKCNSMQSEYREKNVERIRRQLKITNAGMVSDEELEQMLDSG
  QSEVFVSNILKDTQVTRQALNEISARHSEIQQLERSIRELHDIFTFLATEVEMQGEMINR
  IEKNILSSADYVERGQEHVKTALENQKKARKKKVLIAICVSITVVLLAVIIGVTVVG
• Function: Plasma membrane t-SNARE that mediates docking of transport vesicles. Necessary for the translocation of SLC2A4 from intracellular vesicles to the plasma membrane. In neurons, recruited at neurite tips to membrane domains rich in the phospholipid 1-oleoyl-2-palmitoyl-PC (OPPC) which promotes neurite tip surface expression of the dopamine transporter SLC6A3/DAT by facilitating fusion of SLC6A3-containing transport vesicles with the plasma membrane. Together with STXB3 and VAMP2, may also play a role in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes and in docking of synaptic vesicles at presynaptic active zones.
• Tissue Specificity: Expressed in neutrophils and neutrophil-differentiated HL-60 cells. Expression in neutrophils increases with differentiation.
• KEGG Pathway:
  S.RE interactions in vesicular transport (hsa04130)
  Vasopressin-regulated water reabsorption (hsa04962)
• Reactome Pathway:
  ER-Phagosome pathway (R-HSA-1236974)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)
  trans-Golgi Network Vesicle Budding (R-HSA-199992)
  Other interleukin signaling (R-HSA-449836)
  Disinhibition of SNARE formation (R-HSA-114516)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Syntaxin-4 (STX4).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Syntaxin-4 (STX4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Syntaxin-4 (STX4).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Syntaxin-4 (STX4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Syntaxin-4 (STX4).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Syntaxin-4 (STX4).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Syntaxin-4 (STX4).	[13]

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 Syntaxin-4 (STX4).	[14]

References

• [1] Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition.Front Immunol. 2018 May 29;9:1186. doi: 10.3389/fimmu.2018.01186. eCollection 2018.
• [2] Identification of syntaxin 4 as an essential factor for the hepatitis C virus life cycle.Eur J Cell Biol. 2017 Sep;96(6):542-552. doi: 10.1016/j.ejcb.2017.06.002. Epub 2017 Jun 10.
• [3] De-regulation of diabetic regulatory genes in psoriasis: Deciphering the unsolved riddle.Gene. 2016 Nov 15;593(1):110-116. doi: 10.1016/j.gene.2016.08.024. Epub 2016 Aug 13.
• [4] Syntaxin-4 is essential for IgE secretion by plasma cells.Biochem Biophys Res Commun. 2013 Oct 11;440(1):163-7. doi: 10.1016/j.bbrc.2013.09.058. Epub 2013 Sep 18.
• [5] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [6] Syntaxin 4 Expression in Pancreatic -Cells Promotes Islet Function and Protects Functional -Cell Mass.Diabetes. 2018 Dec;67(12):2626-2639. doi: 10.2337/db18-0259. Epub 2018 Oct 10.
• [7] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.