Details of Drug Off-Target (DOT)

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

• DOT Name: Sphingosine-1-phosphate transporter SPNS2 (SPNS2)
• Synonyms: Protein spinster homolog 2
• Gene Name: SPNS2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Colorectal carcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Relapsing-remitting multiple sclerosis
  Autoimmune disease
  Hearing loss, autosomal recessive 115
  Pancreatic cancer
• UniProt ID: SPNS2_HUMAN
• PDB ID: 7YUB; 7YUD; 7YUF; 8EX4; 8EX5; 8EX6; 8EX7; 8EX8; 8G92
• Pfam ID: PF07690
• Sequence:
  MMCLECASAAAGGAEEEEADAERRRRRRGAQRGAGGSGCCGARGAGGAGVSAAGDEVQTL
  SGSVRRAPTGPPGTPGTPGCAATAKGPGAQQPKPASLGRGRGAAAAILSLGNVLNYLDRY
  TVAGVLLDIQQHFGVKDRGAGLLQSVFICSFMVAAPIFGYLGDRFNRKVILSCGIFFWSA
  VTFSSSFIPQQYFWLLVLSRGLVGIGEASYSTIAPTIIGDLFTKNTRTLMLSVFYFAIPL
  GSGLGYITGSSVKQAAGDWHWALRVSPVLGMITGTLILILVPATKRGHADQLGDQLKART
  SWLRDMKALIRNRSYVFSSLATSAVSFATGALGMWIPLYLHRAQVVQKTAETCNSPPCGA
  KDSLIFGAITCFTGFLGVVTGAGATRWCRLKTQRADPLVCAVGMLGSAIFICLIFVAAKS
  SIVGAYICIFVGETLLFSNWAITADILMYVVIPTRRATAVALQSFTSHLLGDAGSPYLIG
  FISDLIRQSTKDSPLWEFLSLGYALMLCPFVVVLGGMFFLATALFFVSDRARAEQQVNQL
  AMPPASVKV
• Function: Lipid transporter that specifically mediates export of sphingosine-1-phosphate (sphing-4-enine 1-phosphate, S1P) and sphinganine-1-phosphate in the lymph, thereby playing a role in lymphocyte trafficking. S1P is a bioactive signaling molecule that regulates many physiological processes important for the development and for the immune system. Regulates levels of S1P and the S1P gradient that exists between the high circulating concentrations of S1P and low tissue levels that control lymphocyte trafficking. Required for the egress of T-cells from lymph nodes during an immune response by mediating S1P secretion, which generates a gradient that enables activated T-cells to access lymph. Also required for the egress of immature B-cells from the bone marrow. In contrast, not involved in S1P release from red blood cells. Involved in auditory function. S1P release in the inner ear is required for maintenance of the endocochlear potential in the cochlea. In addition to export, also able to mediate S1P import.
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

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	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung carcinoma	DISTR26C	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Relapsing-remitting multiple sclerosis	DISSXFCF	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	moderate	Biomarker	[4]
Hearing loss, autosomal recessive 115	DIS7CFPD	Moderate	Autosomal recessive	[5]
Pancreatic cancer	DISJC981	moderate	Biomarker	[6]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sphingosine-1-Phosphate	DMJCQKA	Phase 1	Sphingosine-1-phosphate transporter SPNS2 (SPNS2) increases the secretion of Sphingosine-1-Phosphate.	[18]
dihydrosphingosine-1-phosphate	DM58KHY	Investigative	Sphingosine-1-phosphate transporter SPNS2 (SPNS2) decreases the abundance of dihydrosphingosine-1-phosphate.	[18]

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 Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[11]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[16]
GW7647	DM9RD0C	Investigative	GW7647 increases the expression of Sphingosine-1-phosphate transporter SPNS2 (SPNS2).	[17]

References

• [1] SPNS2 promotes the malignancy of colorectal cancer cells via regulating Akt and ERK pathway.Clin Exp Pharmacol Physiol. 2019 Sep;46(9):861-871. doi: 10.1111/1440-1681.13124. Epub 2019 Jun 30.
• [2] Lipid transporter Spns2 promotes microglia pro-inflammatory activation in response to amyloid-beta peptide.Glia. 2019 Mar;67(3):498-511. doi: 10.1002/glia.23558. Epub 2018 Nov 28.
• [3] Critical role of Spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration.PLoS One. 2014 Oct 20;9(10):e110119. doi: 10.1371/journal.pone.0110119. eCollection 2014.
• [4] New insights into functions of the sphingosine-1-phosphate transporter SPNS2.J Lipid Res. 2019 Mar;60(3):484-489. doi: 10.1194/jlr.S091959. Epub 2019 Jan 17.
• [5] Mouse screen reveals multiple new genes underlying mouse and human hearing loss. PLoS Biol. 2019 Apr 11;17(4):e3000194. doi: 10.1371/journal.pbio.3000194. eCollection 2019 Apr.
• [6] Identification of lncRNAs and Their Functional Network Associated with Chemoresistance in SW1990/GZ Pancreatic Cancer Cells by RNA Sequencing.DNA Cell Biol. 2018 Oct;37(10):839-849. doi: 10.1089/dna.2018.4312. Epub 2018 Aug 16.
• [7] 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.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [15] 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.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Identifying qualitative differences in PPAR signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods. Toxicol In Vitro. 2020 Apr;64:104463. doi: 10.1016/j.tiv.2019.02.017. Epub 2019 Oct 15.
• [18] Downregulation of the S1P Transporter Spinster Homology Protein 2 (Spns2) Exerts an Anti-Fibrotic and Anti-Inflammatory Effect in Human Renal Proximal Tubular Epithelial Cells. Int J Mol Sci. 2018 May 17;19(5):1498. doi: 10.3390/ijms19051498.