Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCVF6MM)

• DOT Name: Signal peptide peptidase-like 2A (SPPL2A)
• Synonyms: SPP-like 2A; SPPL2a; EC 3.4.23.-; Intramembrane protease 3; IMP-3; Presenilin-like protein 2
• Gene Name: SPPL2A
• Related Disease:
  Mycobacterium infection
  Alzheimer disease
  Autoimmune disease
  Esophageal squamous cell carcinoma
  Gastric cancer
  Gastric neoplasm
  Melanoma
  Neoplasm
  Stomach cancer
  Advanced cancer
  Epithelioid mesothelioma
  Immunodeficiency 86
• UniProt ID: SPP2A_HUMAN
• EC Number: 3.4.23.-
• Pfam ID: PF02225 ; PF04258
• Sequence:
  MGPQRRLSPAGAALLWGFLLQLTAAQEAILHASGNGTTKDYCMLYNPYWTALPSTLENAT
  SISLMNLTSTPLCNLSDIPPVGIKSKAVVVPWGSCHFLEKARIAQKGGAEAMLVVNNSVL
  FPPSGNRSEFPDVKILIAFISYKDFRDMNQTLGDNITVKMYSPSWPNFDYTMVVIFVIAV
  FTVALGGYWSGLVELENLKAVTTEDREMRKKKEEYLTFSPLTVVIFVVICCVMMVLLYFF
  YKWLVYVMIAIFCIASAMSLYNCLAALIHKIPYGQCTIACRGKNMEVRLIFLSGLCIAVA
  VVWAVFRNEDRWAWILQDILGIAFCLNLIKTLKLPNFKSCVILLGLLLLYDVFFVFITPF
  ITKNGESIMVELAAGPFGNNEKLPVVIRVPKLIYFSVMSVCLMPVSILGFGDIIVPGLLI
  AYCRRFDVQTGSSYIYYVSSTVAYAIGMILTFVVLVLMKKGQPALLYLVPCTLITASVVA
  WRRKEMKKFWKGNSYQMMDHLDCATNEENPVISGEQIVQQ
• Function: Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane signal peptides in the hydrophobic plane of the membrane. Functions in FASLG, ITM2B and TNF processing. Catalyzes the intramembrane cleavage of the anchored fragment of shed TNF-alpha (TNF), which promotes the release of the intracellular domain (ICD) for signaling to the nucleus. Also responsible for the intramembrane cleavage of Fas antigen ligand FASLG, which promotes the release of the intracellular FasL domain (FasL ICD). Essential for degradation of the invariant chain CD74 that plays a central role in the function of antigen-presenting cells in the immune system. Plays a role in the regulation of innate and adaptive immunity. Catalyzes the intramembrane cleavage of the simian foamy virus envelope glycoprotein gp130 independently of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: Regulation of TNFR1 signaling (R-HSA-5357905)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mycobacterium infection	DISNSMUD	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[5]
Melanoma	DIS1RRCY	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[7]
Epithelioid mesothelioma	DIS17SNY	Limited	Biomarker	[8]
Immunodeficiency 86	DIS3VZ38	Limited	Autosomal recessive	[1]

2 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 Signal peptide peptidase-like 2A (SPPL2A).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Signal peptide peptidase-like 2A (SPPL2A).	[18]

10 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 Signal peptide peptidase-like 2A (SPPL2A).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Signal peptide peptidase-like 2A (SPPL2A).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Signal peptide peptidase-like 2A (SPPL2A).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Signal peptide peptidase-like 2A (SPPL2A).	[20]

References

• [1] Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol. 2018 Sep;19(9):973-985. doi: 10.1038/s41590-018-0178-z. Epub 2018 Aug 20.
• [2] Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of -Secretase.J Neurosci. 2019 Oct 23;39(43):8600-8610. doi: 10.1523/JNEUROSCI.0838-19.2019. Epub 2019 Sep 16.
• [3] Discovery of the First Potent, Selective, and Orally Bioavailable Signal Peptide Peptidase-Like 2a (SPPL2a) Inhibitor Displaying Pronounced Immunomodulatory Effects In Vivo.J Med Chem. 2018 Feb 8;61(3):865-880. doi: 10.1021/acs.jmedchem.7b01371. Epub 2018 Jan 23.
• [4] Prognostic significance of IMP-3 expression pattern in esophageal squamous cell carcinoma.J Thorac Dis. 2019 Sep;11(9):3776-3784. doi: 10.21037/jtd.2019.09.25.
• [5] Oncofetal protein, IMP-3, a potential marker for prediction of postoperative peritoneal dissemination in gastric adenocarcinoma.J Surg Oncol. 2012 Jun 15;105(8):780-5. doi: 10.1002/jso.22108. Epub 2011 Oct 19.
• [6] Investigation of IGF2/ApaI and H19/RsaI polymorphisms in patients with cutaneous melanoma.Growth Horm IGF Res. 2010 Aug;20(4):295-7. doi: 10.1016/j.ghir.2010.03.006. Epub 2010 May 18.
• [7] Post-transcriptional regulation of cyclins D1, D3 and G1 and proliferation of human cancer cells depend on IMP-3 nuclear localization.Oncogene. 2014 May 29;33(22):2866-75. doi: 10.1038/onc.2013.252. Epub 2013 Jul 1.
• [8] Use of Anti-Noxa Antibody for Differential Diagnosis between Epithelioid Mesothelioma and Reactive Mesothelial Hyperplasia.Pathobiology. 2016;83(1):33-40. doi: 10.1159/000442092. Epub 2016 Jan 7.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] 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.
• [17] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [18] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.