Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WB1YB)

• DOT Name: Dual specificity protein phosphatase 12 (DUSP12)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Dual specificity tyrosine phosphatase YVH1
• Gene Name: DUSP12
• Related Disease:
  Advanced cancer
  Autoimmune disease
  Dilated cardiomyopathy 1A
  Fatty liver disease
  Hyperinsulinemia
  Malignant soft tissue neoplasm
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Sarcoma
  Type-1/2 diabetes
  Bacterial infection
• UniProt ID: DUS12_HUMAN
• PDB ID: 4JNB; 4KI9
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782
• Sequence:
  MLEAPGPSDGCELSNPSASRVSCAGQMLEVQPGLYFGGAAAVAEPDHLREAGITAVLTVD
  SEEPSFKAGPGVEDLWRLFVPALDKPETDLLSHLDRCVAFIGQARAEGRAVLVHCHAGVS
  RSVAIITAFLMKTDQLPFEKAYEKLQILKPEAKMNEGFEWQLKLYQAMGYEVDTSSAIYK
  QYRLQKVTEKYPELQNLPQELFAVDPTTVSQGLKDEVLYKCRKCRRSLFRSSSILDHREG
  SGPIAFAHKRMTPSSMLTTGRQAQCTSYFIEPVQWMESALLGVMDGQLLCPKCSAKLGSF
  NWYGEQCSCGRWITPAFQIHKNRVDEMKILPVLGSQTGKI
• Function: Dual specificity phosphatase; can dephosphorylate both phosphotyrosine and phosphoserine or phosphothreonine residues. Can dephosphorylate glucokinase (in vitro). Has phosphatase activity with the synthetic substrate 6,8-difluoro-4-methylumbelliferyl phosphate and other in vitro substrates.
• Tissue Specificity: Ubiquitous, highest expression in spleen, testis, ovary, and peripheral blood leukocytes and lower expression in liver and lung.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[3]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[4]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[4]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[5]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[6]
Sarcoma	DISZDG3U	Strong	Biomarker	[5]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[3]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Dual specificity protein phosphatase 12 (DUSP12).	[8]

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 Dual specificity protein phosphatase 12 (DUSP12).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity protein phosphatase 12 (DUSP12).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity protein phosphatase 12 (DUSP12).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dual specificity protein phosphatase 12 (DUSP12).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dual specificity protein phosphatase 12 (DUSP12).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity protein phosphatase 12 (DUSP12).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Dual specificity protein phosphatase 12 (DUSP12).	[15]

References

• [1] PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers.Oncol Rep. 2004 Mar;11(3):655-9.
• [2] MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus.Cells. 2019 Nov 13;8(11):1433. doi: 10.3390/cells8111433.
• [3] MicroRNA-200c modulates DUSP-1 expression in diabetes-induced cardiac hypertrophy.Mol Cell Biochem. 2017 Jan;424(1-2):1-11. doi: 10.1007/s11010-016-2838-3. Epub 2016 Sep 30.
• [4] Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.Hepatology. 2019 Oct;70(4):1099-1118. doi: 10.1002/hep.30597. Epub 2019 Apr 22.
• [5] Mapping and characterization of the amplicon near APOA2 in 1q23 in human sarcomas by FISH and array CGH.Mol Cancer. 2005 Nov 7;4:39. doi: 10.1186/1476-4598-4-39.
• [6] Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population.BMC Med Genet. 2011 Jan 6;12:3. doi: 10.1186/1471-2350-12-3.
• [7] Dual-Specificity Phosphatase 12 Targets p38 MAP Kinase to Regulate Macrophage Response to Intracellular Bacterial Infection.Front Immunol. 2017 Oct 9;8:1259. doi: 10.3389/fimmu.2017.01259. eCollection 2017.
• [8] 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.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.