Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2HLJF6)

• DOT Name: Signal peptide peptidase-like 3 (SPPL3)
• Synonyms: SPP-like 3; EC 3.4.23.-; Intramembrane protease 2; IMP-2; Presenilin homologous protein 1; PSH1; Presenilin-like protein 4
• Gene Name: SPPL3
• Related Disease:
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Ovarian cancer
  Ovarian neoplasm
  Adenoma
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Liposarcoma
  Liver cirrhosis
  Major depressive disorder
  Neoplasm
  Non-insulin dependent diabetes
  Triple negative breast cancer
  Advanced cancer
  Allergic rhinitis
  Fatty liver disease
  Obesity
  Polycystic ovarian syndrome
  Systemic lupus erythematosus
  Malaria
  Gallbladder carcinoma
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: SPPL3_HUMAN
• EC Number: 3.4.23.-
• Pfam ID: PF04258
• Sequence:
  MAEQTYSWAYSLVDSSQVSTFLISILLIVYGSFRSLNMDFENQDKEKDSNSSSGSFNGNS
  TNNSIQTIDSTQALFLPIGASVSLLVMFFFFDSVQVVFTICTAVLATIAFAFLLLPMCQY
  LTRPCSPQNKISFGCCGRFTAAELLSFSLSVMLVLIWVLTGHWLLMDALAMGLCVAMIAF
  VRLPSLKVSCLLLSGLLIYDVFWVFFSAYIFNSNVMVKVATQPADNPLDVLSRKLHLGPN
  VGRDVPRLSLPGKLVFPSSTGSHFSMLGIGDIVMPGLLLCFVLRYDNYKKQASGDSCGAP
  GPANISGRMQKVSYFHCTLIGYFVGLLTATVASRIHRAAQPALLYLVPFTLLPLLTMAYL
  KGDLRRMWSEPFHSKSSSSRFLEV
• Function: Intramembrane-cleaving aspartic protease (I-CLiP) that cleaves type II membrane protein substrates in or close to their luminal transmembrane domain boundaries. Acts like a sheddase by mediating the proteolytic release and secretion of active site-containing ectodomains of glycan-modifiying glycosidase and glycosyltransferase enzymes such as MGAT5, B4GAT1 and B4GALT1. Catalyzes the intramembrane cleavage of the envelope glycoprotein gp130 and/or the leader peptide gp18LP of the simian foamy virus independent of prior ectodomain shedding by furin or furin-like proprotein convertase (PC)-mediated cleavage proteolysis. May also have the ability to serve as a shedding protease for subsequent intramembrane proteolysis by SPPL2A and SPPL2B of the envelope glycoprotein gp130. Plays a role in the regulation of cellular glycosylation processes. Required to link T-cell antigen receptor (TCR) and calcineurin-NFAT signaling cascades in lymphocytes by promoting the association of STIM1 and ORAI1 during store-operated calcium entry (SOCE) in a protease-independent manner.
• Tissue Specificity: Widely expressed . Expressed in the brain .

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[5]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[6]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[5]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[9]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[11]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[12]
Fatty liver disease	DIS485QZ	moderate	Genetic Variation	[5]
Obesity	DIS47Y1K	moderate	Biomarker	[13]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Biomarker	[14]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[15]
Malaria	DISQ9Y50	Disputed	Biomarker	[16]
Gallbladder carcinoma	DISD6ACL	Limited	Biomarker	[8]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[17]
Pancreatic cancer	DISJC981	Limited	Biomarker	[17]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Signal peptide peptidase-like 3 (SPPL3).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Signal peptide peptidase-like 3 (SPPL3).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Signal peptide peptidase-like 3 (SPPL3).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Signal peptide peptidase-like 3 (SPPL3).	[18]
Marinol	DM70IK5	Approved	Marinol increases the expression of Signal peptide peptidase-like 3 (SPPL3).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Signal peptide peptidase-like 3 (SPPL3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Signal peptide peptidase-like 3 (SPPL3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Signal peptide peptidase-like 3 (SPPL3).	[23]

References

• [1] The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing.Cell Rep. 2016 May 24;15(8):1634-47. doi: 10.1016/j.celrep.2016.04.086. Epub 2016 May 12.
• [2] p62/IMP2 stimulates cell migration and reduces cell adhesion in breast cancer.Oncotarget. 2015 Oct 20;6(32):32656-68. doi: 10.18632/oncotarget.5328.
• [3] Humoral autoimmune responses to insulin-like growth factor II mRNA-binding proteins IMP1 and p62/IMP2 in ovarian cancer.J Immunol Res. 2014;2014:326593. doi: 10.1155/2014/326593. Epub 2014 Apr 27.
• [4] Humoral autoimmune response to IGF2 mRNA-binding protein (IMP2/p62) and its tissue-specific expression in colon cancer.Scand J Immunol. 2013 Apr;77(4):255-60. doi: 10.1111/sji.12032.
• [5] IGF2 mRNA Binding Protein 2 Transgenic Mice Are More Prone to Develop a Ductular Reaction and to Progress Toward Cirrhosis.Front Med (Lausanne). 2019 Sep 4;6:179. doi: 10.3389/fmed.2019.00179. eCollection 2019.
• [6] HMGA2 regulates transcription of the Imp2 gene via an intronic regulatory element in cooperation with nuclear factor-kappaB.Mol Cancer Res. 2007 Apr;5(4):363-72. doi: 10.1158/1541-7786.MCR-06-0331.
• [7] Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.Nat Neurosci. 2019 Mar;22(3):343-352. doi: 10.1038/s41593-018-0326-7. Epub 2019 Feb 4.
• [8] IMP2/IGF2BP2 expression, but not IMP1 and IMP3, predicts poor outcome in patients and high tumor growth rate in xenograft models of gallbladder cancer.Oncotarget. 2017 Sep 21;8(52):89736-89745. doi: 10.18632/oncotarget.21116. eCollection 2017 Oct 27.
• [9] Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.
• [10] IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor.Cancer Lett. 2018 Feb 28;415:30-39. doi: 10.1016/j.canlet.2017.11.039. Epub 2017 Dec 5.
• [11] Transgenic expression of the RNA binding protein IMP2 stabilizes miRNA targets in murine microsteatosis.Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3099-3108. doi: 10.1016/j.bbadis.2018.05.024. Epub 2018 May 30.
• [12] Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018 Aug;50(8):1072-1080. doi: 10.1038/s41588-018-0157-1. Epub 2018 Jul 16.
• [13] Liver-specific deletion of IGF2 mRNA binding protein-2/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation.J Biol Chem. 2019 Aug 2;294(31):11944-11951. doi: 10.1074/jbc.RA119.008778. Epub 2019 Jun 17.
• [14] The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome.J Clin Endocrinol Metab. 2019 Apr 1;104(4):1049-1059. doi: 10.1210/jc.2018-00544.
• [15] A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus.Nat Genet. 2009 Nov;41(11):1228-33. doi: 10.1038/ng.468. Epub 2009 Oct 18.
• [16] Intramembrane proteolytic cleavage by human signal peptide peptidase like 3 and malaria signal peptide peptidase.FASEB J. 2006 Aug;20(10):1671-9. doi: 10.1096/fj.06-5762com.
• [17] The Insulin-Like Growth Factor 2 mRNA Binding Protein IMP2/IGF2BP2 is Overexpressed and Correlates with Poor Survival in Pancreatic Cancer.Int J Mol Sci. 2019 Jun 29;20(13):3204. doi: 10.3390/ijms20133204.
• [18] 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.
• [19] 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.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [24] 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.