Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT45TMC4)

• DOT Name: E3 ubiquitin-protein ligase Praja-2 (PJA2)
• Synonyms: Praja2; EC 2.3.2.27; RING finger protein 131; RING-type E3 ubiquitin transferase Praja-2
• Gene Name: PJA2
• Related Disease:
  Advanced cancer
  Differentiated thyroid carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  Breast carcinoma
• UniProt ID: PJA2_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF13639
• Sequence:
  MSQYTEKEPAAMDQESGKAVWPKPAGGYQTITGRRYGRRHAYVSFKPCMTRHERSLGRAG
  DDYEVLELDDVPKENSSGSSPLDQVDSSLPSEPIFEKSETEIPTCGSALNQTTESSQSFV
  AVHHSEEGRDTLGSSTNLHNHSEGEYIPGACSASSVQNGIALVHTDSYDPDGKHGEDNDH
  LQLSAEVVEGSRYQESLGNTVFELENREAEAYTGLSPPVPSFNCEVRDEFEELDSVPLVK
  SSAGDTEFVHQNSQEIQRSSQDEMVSTKQQNNTSQERQTEHSPEDAACGPGHICSEQNTN
  DREKNHGSSPEQVVRPKVRKLISSSQVDQETGFNRHEAKQRSVQRWREALEVEESGSDDL
  LIKCEEYDGEHDCMFLDPPYSRVITQRETENNQMTSESGATAGRQEVDNTFWNGCGDYYQ
  LYDKDEDSSECSDGEWSASLPHRFSGTEKDQSSSDESWETLPGKDENEPELQSDSSGPEE
  ENQELSLQEGEQTSLEEGEIPWLQYNEVNESSSDEGNEPANEFAQPAFMLDGNNNLEDDS
  SVSEDLDVDWSLFDGFADGLGVAEAISYVDPQFLTYMALEERLAQAMETALAHLESLAVD
  VEVANPPASKESIDGLPETLVLEDHTAIGQEQCCPICCSEYIKDDIATELPCHHFFHKPC
  VSIWLQKSGTCPVCRRHFPPAVIEASAAPSSEPDPDAPPSNDSIAEAP
• Function: Has E2-dependent E3 ubiquitin-protein ligase activity. Responsible for ubiquitination of cAMP-dependent protein kinase type I and type II-alpha/beta regulatory subunits and for targeting them for proteasomal degradation. Essential for PKA-mediated long-term memory processes. Through the ubiquitination of MFHAS1, positively regulates the TLR2 signaling pathway that leads to the activation of the downstream p38 and JNK MAP kinases and promotes the polarization of macrophages toward the pro-inflammatory M1 phenotype. Plays a role in ciliogenesis by ubiquitinating OFD1.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[1]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[1]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[1]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[2]

11 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 E3 ubiquitin-protein ligase Praja-2 (PJA2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[8]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of E3 ubiquitin-protein ligase Praja-2 (PJA2).	[15]

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 E3 ubiquitin-protein ligase Praja-2 (PJA2).	[13]

References

• [1] Expression of the ring ligase PRAJA2 in thyroid cancer.J Clin Endocrinol Metab. 2012 Nov;97(11):4253-9. doi: 10.1210/jc.2012-2360. Epub 2012 Sep 4.
• [2] CD1d- and PJA2-related immune microenvironment differs between invasive breast carcinomas with and without a micropapillary feature.BMC Cancer. 2019 Jan 16;19(1):76. doi: 10.1186/s12885-018-5221-9.
• [3] Detection of novel paraja ring finger 2-fer tyrosine kinase mRNA chimeras is associated with poor postoperative prognosis in non-small cell lung cancer.Cancer Sci. 2013 Nov;104(11):1447-54. doi: 10.1111/cas.12250. Epub 2013 Sep 5.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [8] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [9] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.