Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAK3VFR)

• DOT Name: Signal transducer and activator of transcription 4 (STAT4)
• Gene Name: STAT4
• Related Disease:
  Ankylosing spondylitis
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease, susceptibility to, 6
  Behcet disease
  Chronic obstructive pulmonary disease
  Coeliac disease
  Colorectal carcinoma
  Gastric cancer
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Hypothyroidism
  IgA nephropathy
  Lupus
  Mycosis fungoides
  Myocardial infarction
  Myositis disease
  Nephritis
  Non-typhoidal salmonella
  Psoriasis
  STAT3-related early-onset multisystem autoimmune disease
  Stomach cancer
  Systemic sclerosis
  Vitiligo
  Adult lymphoma
  Immune system disorder
  Lymphoma
  Pediatric lymphoma
  Arthritis
  Chronic hepatitis B virus infection
  Disabling pansclerotic morphea of childhood
  Hepatitis C virus infection
  Inflammatory bowel disease
  Lupus nephritis
  Multiple sclerosis
  Obesity
  Primary biliary cholangitis
  Pulmonary fibrosis
  Sjogren syndrome
• UniProt ID: STAT4_HUMAN
• Pfam ID: PF00017 ; PF01017 ; PF02864 ; PF02865 ; PF21354
• Sequence:
  MSQWNQVQQLEIKFLEQVDQFYDDNFPMEIRHLLAQWIENQDWEAASNNETMATILLQNL
  LIQLDEQLGRVSKEKNLLLIHNLKRIRKVLQGKFHGNPMHVAVVISNCLREERRILAAAN
  MPVQGPLEKSLQSSSVSERQRNVEHKVAAIKNSVQMTEQDTKYLEDLQDEFDYRYKTIQT
  MDQSDKNSAMVNQEVLTLQEMLNSLDFKRKEALSKMTQIIHETDLLMNTMLIEELQDWKR
  RQQIACIGGPLHNGLDQLQNCFTLLAESLFQLRRQLEKLEEQSTKMTYEGDPIPMQRTHM
  LERVTFLIYNLFKNSFVVERQPCMPTHPQRPLVLKTLIQFTVKLRLLIKLPELNYQVKVK
  ASIDKNVSTLSNRRFVLCGTNVKAMSIEESSNGSLSVEFRHLQPKEMKSSAGGKGNEGCH
  MVTEELHSITFETQICLYGLTIDLETSSLPVVMISNVSQLPNAWASIIWYNVSTNDSQNL
  VFFNNPPPATLSQLLEVMSWQFSSYVGRGLNSDQLHMLAEKLTVQSSYSDGHLTWAKFCK
  EHLPGKSFTFWTWLEAILDLIKKHILPLWIDGYVMGFVSKEKERLLLKDKMPGTFLLRFS
  ESHLGGITFTWVDHSESGEVRFHSVEPYNKGRLSALPFADILRDYKVIMAENIPENPLKY
  LYPDIPKDKAFGKHYSSQPCEVSRPTERGDKGYVPSVFIPISTIRSDSTEPHSPSDLLPM
  SPSVYAVLRENLSPTTIETAMKSPYSAE
• Function: Transcriptional regulator mainly expressed in hematopoietic cells that plays a critical role in cellular growth, differentiation and immune response. Plays a key role in the differentiation of T-helper 1 cells and the production of interferon-gamma. Participates also in multiple neutrophil functions including chemotaxis and production of the neutrophil extracellular traps. After IL12 binding to its receptor IL12RB2, STAT4 interacts with the intracellular domain of IL12RB2 and becomes tyrosine phosphorylated. Phosphorylated STAT4 then homodimerizes and migrates to the nucleus where it can recognize STAT target sequences present in IL12 responsive genes. Although IL12 appears to be the predominant activating signal, STAT4 can also be phosphorylated and activated in response to IFN-gamma stimulation via JAK1 and TYK2 and in response to different interleukins including IL23, IL2 and IL35. Transcription activation of IFN-gamma gene is mediated by interaction with JUN that forms a complex that efficiently interacts with the AP-1-related sequence of the IFN-gamma promoter. In response to IFN-alpha/beta signaling, acts as a transcriptional repressor and suppresses IL5 and IL13 mRNA expression during response to T-cell receptor (TCR) activation.
• KEGG Pathway:
  Necroptosis (hsa04217)
  JAK-STAT sig.ling pathway (hsa04630)
  Th1 and Th2 cell differentiation (hsa04658)
  Hepatitis B (hsa05161)
  Pathways in cancer (hsa05200)
  Inflammatory bowel disease (hsa05321)
• Reactome Pathway:
  Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation (R-HSA-8950505)
  Interleukin-35 Signalling (R-HSA-8984722)
  Interleukin-12 signaling (R-HSA-9020591)
  Interleukin-23 signaling (R-HSA-9020933)
  Interleukin-21 signaling (R-HSA-9020958)
  Interleukin-20 family signaling (R-HSA-8854691)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Autoimmune disease, susceptibility to, 6	DISHNUXI	Strong	Genetic Variation	[3]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[4]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[5]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[10]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[3]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[11]
Lupus	DISOKJWA	Strong	Genetic Variation	[12]
Mycosis fungoides	DIS62RB8	Strong	Altered Expression	[13]
Myocardial infarction	DIS655KI	Strong	Biomarker	[14]
Myositis disease	DISCIXF0	Strong	Genetic Variation	[15]
Nephritis	DISQZQ70	Strong	Biomarker	[14]
Non-typhoidal salmonella	DISBCAC5	Strong	Genetic Variation	[16]
Psoriasis	DIS59VMN	Strong	Altered Expression	[17]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[15]
Vitiligo	DISR05SL	Strong	Genetic Variation	[18]
Adult lymphoma	DISK8IZR	moderate	Altered Expression	[19]
Immune system disorder	DISAEGPH	moderate	Genetic Variation	[20]
Lymphoma	DISN6V4S	moderate	Altered Expression	[19]
Pediatric lymphoma	DIS51BK2	moderate	Altered Expression	[19]
Arthritis	DIST1YEL	Limited	Genetic Variation	[21]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Genetic Variation	[22]
Disabling pansclerotic morphea of childhood	DISK97M3	Limited	Autosomal dominant	[23]
Hepatitis C virus infection	DISQ0M8R	Limited	Genetic Variation	[24]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[25]
Lupus nephritis	DISCVGPZ	Limited	Genetic Variation	[26]
Multiple sclerosis	DISB2WZI	Limited	Biomarker	[27]
Obesity	DIS47Y1K	Limited	Therapeutic	[28]
Primary biliary cholangitis	DIS43E0O	Limited	Biomarker	[29]
Pulmonary fibrosis	DISQKVLA	Limited	Biomarker	[30]
Sjogren syndrome	DISUBX7H	Limited	Genetic Variation	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[32]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[34]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[36]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[38]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[39]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[40]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[40]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[41]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[40]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[42]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[40]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[44]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[45]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[43]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Signal transducer and activator of transcription 4 (STAT4).	[46]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Signal transducer and activator of transcription 4 (STAT4).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Signal transducer and activator of transcription 4 (STAT4).	[37]

References

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