New insights into functions of the sphingosine-1-phosphate transporter SPNS2

The role of sphingosine-1-phosphate (S1P) as a bioactive sphingolipid metabolite was discovered in our lab almost 3 decades ago (1.Zhang H. Desai N.N. Olivera A. Seki T. Brooker G. Spiegel S. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation.J. Cell Biol. 1991; 114: 155-167Crossref PubMed Scopus (564) Google Scholar, 2.Olivera A. Spiegel S. Sphingosine-1-phosphate as a second messenger in cell proliferation induced by PDGF and FCS mitogens.Nature. 1993; 365: 557-560Crossref PubMed Scopus (814) Google Scholar). However, its pleiotropic actions remained enigmatic until, together with Timothy Hla, who originally cloned endothelial differentiation gene 1 as an immediate early gene induced during the differentiation of endothelial cells (3.Hla T. Maciag T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein coupled receptors.J. Biol. Chem. 1990; 265: 9308-9313Abstract Full Text PDF PubMed Google Scholar), we showed that this is a bona fide S1P receptor (S1PR1) (4.Lee M.J. Van Brocklyn J.R. Thangada S. Liu C.H. Hand A.R. Menzeleev R. Spiegel S. Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1.Science. 1998; 279: 1552-1555Crossref PubMed Scopus (886) Google Scholar, 5.Van Brocklyn J.R. Lee M.J. Menzeleev R. Olivera A. Edsall L. Cuvillier O. Thomas D.M. Coopman P.J.P. Thangada S. Hla T. et al.Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled orphan receptor edg-1 and intracellular to regulate proliferation and survival.J. Cell Biol. 1998; 142: 229-240Crossref PubMed Scopus (446) Google Scholar). This rapidly led to the discovery of a family of five specific cell-surface G protein-coupled receptors (S1PR1–5) that endow S1P with the ability to regulate many important functions (6.Spiegel S. Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid.Nat. Rev. Mol. Cell Biol. 2003; 4: 397-407Crossref PubMed Scopus (1756) Google Scholar) (Fig. 1). The activation of S1PRs leads to a plethora of downstream effects depending on the expression of S1PRs, G proteins, and cell type (7.Rosen H. Stevens R.C. Hanson M. Roberts E. Oldstone M.B. Sphingosine-1-phosphate and its receptors: structure, signaling, and influence.Annu. Rev. Biochem. 2013; 82: 637-662Crossref PubMed Scopus (159) Google Scholar) and has been linked to the regulation of multiple physiological and pathophysiological functions, including cell growth and survival, angiogenesis and lymphangiogenesis, endothelial and epithelial barrier function, lymphocyte function and trafficking, and cancer and metastasis, to name a few (7.Rosen H. Stevens R.C. Hanson M. Roberts E. Oldstone M.B. Sphingosine-1-phosphate and its receptors: structure, signaling, and influence.Annu. Rev. Biochem. 2013; 82: 637-662Crossref PubMed Scopus (159) Google Scholar, 8.Spiegel S. Milstien S. The outs and the ins of sphingosine-1-phosphate in immunity.Nat. Rev. Immunol. 2011; 11: 403-415Crossref PubMed Scopus (585) Google Scholar). S1P is produced in cells by the phosphorylation of sphingosine, the backbone of all sphingolipids, by two sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2. Like other bioactive mediators, levels of S1P are tightly regulated by the balance between its synthesis and degradation by S1P phosphatases and S1P lyase. SphK1 and SphK2 have some overlapping but also distinct functions due to their different intracellular localizations (Fig. 1). SphK1 is mainly cytosolic and translocated to the plasma membrane upon stimulation with growth factors and cytokines. In contrast, SphK2 localizes not only to the plasma membrane but also to the ER, mitochondria, and nucleus. This led to the discoveries that S1P produced by SphK2 in mitochondria and nuclei has important functions in these organelles to regulate respiration (9.Strub G.M. Paillard M. Liang J. Gomez L. Allegood J.C. Hait N.C. Maceyka M. Price M.M. Chen Q. Simpson D.C. et al.Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration.FASEB J. 2011; 25: 600-612Crossref PubMed Scopus (254) Google Scholar), histone acetylation, gene expression, and telomerase stability (10.Hait N.C. Allegood J. Maceyka M. Strub G.M. Harikumar K.B. Singh S.K. Luo C. Marmorstein R. Kordula T. Milstien S. et al.Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate.Science. 2009; 325: 1254-1257Crossref PubMed Scopus (745) Google Scholar, 11.Panneer Selvam S. De Palma R.M. Oaks J.J. Oleinik N. Peterson Y.K. Stahelin R.V. Skordalakes E. Ponnusamy S. Garrett-Mayer E. Smith C.D. et al.Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation.Sci. Signal. 2015; 8: ra58Crossref PubMed Scopus (95) Google Scholar). Importantly, however, it has now been convincingly demonstrated that S1P generated inside cells can act in a paracrine and/or autocrine manner by activating S1PRs in an inside-out signaling manner (12.Takabe K. Spiegel S. Export of sphingosine-1-phosphate and cancer progression.J. Lipid Res. 2014; 55: 1839-1846Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 13.Nishi T. Kobayashi N. Hisano Y. Kawahara A. Yamaguchi A. Molecular and physiological functions of sphingosine 1-phosphate transporters.Biochim. Biophys. Acta. 2014; 1841: 759-765Crossref PubMed Scopus (80) Google Scholar). Thus, a robust mechanism is required to transport S1P out of cells. Several transporters have been identified that can transport S1P across the bilayer, including members of the ABC transporter family (12.Takabe K. Spiegel S. Export of sphingosine-1-phosphate and cancer progression.J. Lipid Res. 2014; 55: 1839-1846Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 13.Nishi T. Kobayashi N. Hisano Y. Kawahara A. Yamaguchi A. Molecular and physiological functions of sphingosine 1-phosphate transporters.Biochim. Biophys. Acta. 2014; 1841: 759-765Crossref PubMed Scopus (80) Google Scholar). This review focuses on recent evidence indicating that spinster homologue 2 (SPNS2), a member of the large major facility superfamily (MFS) of non-ATP-dependent organic ion transporters, is a significant and physiologically relevant transporter of S1P. Emphasis is placed on advances in understanding the physiological actions of SPNS2 in regulating levels of S1P and the S1P gradient that exists between the high circulating concentrations of S1P and low tissue levels and lymphocyte trafficking. We also discuss recent discoveries of the roles of SPNS2 in inflammatory and autoimmune diseases, cancer, and metastasis. The role of SPNS2 in S1P transport was first suggested from studies of zebrafish, in which mutations in the SPNS2 gene were found to induce a split heart phenotype, known as two of hearts, which mimicked the phenotype of a mutation in the S1PR2 homologue miles apart (14.Osborne N. Brand-Arzamendi K. Ober E.A. Jin S.W. Verkade H. Holtzman N.G. Yelon D. Stainier D.Y. The spinster homolog, two of hearts, is required for sphingosine 1-phosphate signaling in zebrafish.Curr. Biol. 2008; 18: 1882-1888Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 15.Kawahara A. Nishi T. Hisano Y. Fukui H. Yamaguchi A. Mochizuki N. The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors.Science. 2009; 323: 524-527Crossref PubMed Scopus (323) Google Scholar). Both of these mutations blocked the migration of cardiac precursor cells toward the midline beneath the endoderm and could be rescued by exogenous S1P or by the expression of the human SPNS2 homologue. Several groups then showed that the overexpression of SPNS2 in mammalian cells increased the secretion of S1P (15.Kawahara A. Nishi T. Hisano Y. Fukui H. Yamaguchi A. Mochizuki N. The sphingolipid transporter spns2 functions in migration of zebrafish myocardial precursors.Science. 2009; 323: 524-527Crossref PubMed Scopus (323) Google Scholar, 17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar), and, conversely, its down-regulation decreased the release of both S1P and dihydro-S1P (17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar), confirming that SPNS2 is a mammalian S1P transporter. In addition to endogenously produced S1P and dihydro-S1P, SPNS2 can also transport S1P analogues such as FTY720 phosphate, but not unphosphorylated sphingoid bases (16.Hisano Y. Kobayashi N. Kawahara A. Yamaguchi A. Nishi T. The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720.J. Biol. Chem. 2011; 286: 1758-1766Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, 17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar). Unlike zebrafish, SPNS2 knockout mice are viable, do not exhibit cardiac defects or embryonic lethality, and are generally normal and fertile (18.Nijnik A. Clare S. Hale C. Chen J. Raisen C. Mottram L. Lucas M. Estabel J. Ryder E. Adissu H. et al.The role of sphingosine-1-phosphate transporter spns2 in immune system function.J. Immunol. 2012; 189: 102-111Crossref PubMed Scopus (77) Google Scholar). However, in addition to alterations in immune cell development and trafficking, discussed at length below, SPNS2 knockouts have postnatal cochlear degeneration and retinal dysmorphogenesis (19.Chen J. Ingham N. Kelly J. Jadeja S. Goulding D. Pass J. Mahajan V.B. Tsang S.H. Nijnik A. Jackson I.J. et al.Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.PLoS Genet. 2014; 10: e1004688Crossref PubMed Scopus (44) Google Scholar). SPNS2 knockout mice rapidly lose endocochlear potential and auditory sensitivity after birth, accompanied by capillary abnormalities, structural changes, and secondary sensory hair loss, leading to profound deafness (19.Chen J. Ingham N. Kelly J. Jadeja S. Goulding D. Pass J. Mahajan V.B. Tsang S.H. Nijnik A. Jackson I.J. et al.Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.PLoS Genet. 2014; 10: e1004688Crossref PubMed Scopus (44) Google Scholar). The cochlear-specific knockout of SPNS2 recapitulates the hearing defect, suggesting that local secretion of S1P in the ear, but not systemically circulating S1P, is responsible for maintaining the cochlear structure (19.Chen J. Ingham N. Kelly J. Jadeja S. Goulding D. Pass J. Mahajan V.B. Tsang S.H. Nijnik A. Jackson I.J. et al.Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.PLoS Genet. 2014; 10: e1004688Crossref PubMed Scopus (44) Google Scholar). SPNS2 knockout mice are also born with their eyes open, leading to corneal ulceration and opacity that make retinal assessment by ophthalmoscopy difficult. However, vascular and retinal neurologic defects were observed in whole-animal knockouts but not when SPNS2 was specifically deleted in ear, blood, or lymph tissue, further implicating the importance of S1P signaling through local production. Rats with an insertional mutation in SPNS2 were also born with their eyes open (20.Fang C. Bian G. Ren P. Xiang J. Song J. Yu C. Zhang Q. Liu L. Chen K. Liu F. et al.S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.FASEB J. 2018; 32: 3597-3613Crossref PubMed Scopus (12) Google Scholar). They had lower levels of S1P in amniotic fluid and in the vitreous humor of the eye, where it correlated with a loss of polarity of retinal progenitor cells and insufficient migration of neurons in the developing retina (20.Fang C. Bian G. Ren P. Xiang J. Song J. Yu C. Zhang Q. Liu L. Chen K. Liu F. et al.S1P transporter SPNS2 regulates proper postnatal retinal morphogenesis.FASEB J. 2018; 32: 3597-3613Crossref PubMed Scopus (12) Google Scholar). The open-eye defect was corrected by an injection of S1P into the amniotic fluid, indicating that SPNS2 plays a role in regulating amniotic S1P levels and in the developing retina. Binding of S1P to S1PRs transactivates epidermal growth factor (EGF) receptor signaling through a complex mechanism causing eyelid closure in developing rats (21.Bian G. Yu C. Liu L. Fang C. Chen K. Ren P. Zhang Q. Liu F. Zhang K. Xue Q. et al.Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling.Sci. Signal. 2018; 11: PubMed Scopus Google Scholar). signaling has been to roles in including and the of and between and E. K.B. C. 1-phosphate (S1P) role in and potential for Res. PubMed Scopus Google Scholar). was that the the expression of SPNS2 on S1P S1P through in the to differentiation and these can also function as an of J. P. A. T. A. M. T. J. J. et by the release of sphingosine 1-phosphate from 2014; PubMed Scopus Google Scholar). and SPNS2 were to be in and during differentiation and that the of S1P signaling led to C. A. A. S. T. F. D. L. of sphingosine 1-phosphate in PubMed Scopus Google Scholar). with which is by increased and of also had increased levels of S1P, suggesting that S1P signaling have in this C. A. A. S. T. F. D. L. of sphingosine 1-phosphate in PubMed Scopus Google Scholar). and are abundant blood cells that are the major of S1P in the blood, recent that SPNS2 is not the S1P transporter on these cells S. S. S. A. Y. T. Y. Y. K. J. et al.The sphingosine-1-phosphate transporter on endothelial cells regulates lymphocyte in 2012; PubMed Scopus Google Scholar, Y. Kobayashi N. Yamaguchi A. Nishi T. SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial 2012; PubMed Scopus Google Scholar). This has now been was that a member of the family of transporters as SPNS2, was responsible for S1P from and and that out in mice plasma S1P levels by J.C. Zhang F. D.M. F. A. T. Kim S. et is for the sphingosine-1-phosphate in and PubMed Scopus Google Scholar). However, endothelial cells can also release S1P by SPNS2 (Fig. knockout of SPNS2 circulating S1P to the as the knockout S. S. S. A. Y. T. Y. Y. K. J. et al.The sphingosine-1-phosphate transporter on endothelial cells regulates lymphocyte in 2012; PubMed Scopus Google Scholar, Y. Kobayashi N. Yamaguchi A. Nishi T. SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial 2012; PubMed Scopus Google Scholar) and had the effects (17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar, Hait N.C. Ramachandran S. Maceyka M. Takabe K. Milstien S. T. Spiegel S. a sphingosine-1-phosphate transporter, plays a role in inflammatory and autoimmune J. 2015; PubMed Scopus Google Scholar), that SPNS2 S1P from endothelial cells to the also that S1P from endothelial cells is important for regulating lymphocyte trafficking. In contrast, in specific of SPNS2 in and endothelial cells also induced but with decreased lymph levels and not plasma S1P A. M. M. J.J. The transporter is required for secretion of lymph but not plasma 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). In a Fang et A. A. R. J. M. of the signaling S1P in lymph cells and regulate their Immunol. 18: PubMed Scopus Google Scholar) found that concentrations of S1P in the of lymph in the and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this the other we observed that the lymph from SPNS2 knockout mice have lymphatic that with of (17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar). these mice had levels of S1P in the blood, had increased S1P in the lymph and lymph (17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar). The in of blood, and lymph S1P levels could be due to different of S1P and in lymph from However, it is that SPNS2 is required for the S1P gradient in the it has a role in a gradient between tissue and lymph further the that are at two of circulating S1P, on in and and on SPNS2 in endothelial cells. In their and Sphingosine-1-phosphate and lymphocyte from Rev. Immunol. 2012; PubMed Scopus Google Scholar) demonstrated that lymphocyte is by and regulated by the gradient of S1P, that concentrations in in The role of signaling in and functions of many of immune cells has been and and the is to on this Sphingosine-1-phosphate and lymphocyte from Rev. Immunol. 2012; PubMed Scopus Google Scholar, M. Spiegel S. in inflammatory 2014; PubMed Scopus Google Scholar). Thus, it is not that evidence to a role of SPNS2 that regulates levels of S1P in the blood in immune cell and Several studies have convincingly demonstrated that mice with a (17.Nagahashi M. Kim E.Y. Yamada A. Ramachandran S. Allegood J.C. Hait N.C. Maceyka M. Milstien S. Takabe K. Spiegel S. Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.FASEB J. 2013; 27: 1001-1011Crossref PubMed Scopus (120) Google Scholar, A. Clare S. Hale C. Chen J. Raisen C. Mottram L. Lucas M. Estabel J. Ryder E. Adissu H. et al.The role of sphingosine-1-phosphate transporter spns2 in immune system function.J. Immunol. 2012; 189: 102-111Crossref PubMed Scopus (77) Google Scholar, Hait N.C. Ramachandran S. Maceyka M. Takabe K. Milstien S. T. Spiegel S. a sphingosine-1-phosphate transporter, plays a role in inflammatory and autoimmune J. 2015; PubMed Scopus Google Scholar) or of SPNS2 S. S. S. A. Y. T. Y. Y. K. J. et al.The sphingosine-1-phosphate transporter on endothelial cells regulates lymphocyte in 2012; PubMed Scopus Google Scholar, Y. Kobayashi N. Yamaguchi A. Nishi T. SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial 2012; PubMed Scopus Google Scholar, A. M. M. J.J. The transporter is required for secretion of lymph but not plasma 2012; Full Text Full Text PDF PubMed Scopus Google Scholar) are and exhibit decreased of and in the blood, suggesting that SPNS2 functions in endothelial cells to the S1P gradient required for and to from their of in mice SPNS2 was not on as by Hait N.C. Ramachandran S. Maceyka M. Takabe K. Milstien S. T. Spiegel S. a sphingosine-1-phosphate transporter, plays a role in inflammatory and autoimmune J. 2015; PubMed Scopus Google Scholar). a major of on SPNS2 has been on regulation of immune cell trafficking, it has been that S1P from lymph endothelial cells by SPNS2 not only but also of through A. Fang Chen C. M. A. J. Hla T. O. et endothelial S1P function and in PubMed Scopus Google Scholar). the loss of SPNS2 has a profound on inflammatory The of SPNS2 immune to (18.Nijnik A. Clare S. Hale C. Chen J. Raisen C. Mottram L. Lucas M. Estabel J. Ryder E. Adissu H. et al.The role of sphingosine-1-phosphate transporter spns2 in immune system function.J. Immunol. 2012; 189: 102-111Crossref PubMed Scopus (77) Google Scholar), sensitivity to and and Hait N.C. Ramachandran S. Maceyka M. Takabe K. Milstien S. T. Spiegel S. a sphingosine-1-phosphate transporter, plays a role in inflammatory and autoimmune J. 2015; PubMed Scopus Google Scholar). The SPNS2 knockout mice are also to induced and have and autoimmune Hait N.C. Ramachandran S. Maceyka M. Takabe K. Milstien S. T. Spiegel S. a sphingosine-1-phosphate transporter, plays a role in inflammatory and autoimmune J. 2015; PubMed Scopus Google Scholar), a that the of human multiple studies important roles for S1P transport in the and development of a of SPNS2 also plays a role in as SPNS2 knockouts have to due to the of cells to from lymph A. A. R. J. M. of the signaling S1P in lymph cells and regulate their Immunol. 18: PubMed Scopus Google Scholar). S1P signaling in this was linked to the activation of an that is with studies indicating that is required for cells to to T. L. J. A. C. L. Y. M. E. E. cell in a sphingosine 1-phosphate Immunol. 8: PubMed Scopus Google Scholar). S1P signaling has been linked to many cellular important for cancer including cell growth and survival, metastasis, and Maceyka M. Milstien S. Spiegel S. the sphingosine-1-phosphate in cancer, and Rev. 2013; PubMed Scopus Google Scholar, M. S. N. C. S. S. of sphingosine 1-phosphate sphingosine and sphingosine in cancer and Biol. PubMed Scopus Google Scholar, in cancer signalling and Rev. 2018; 18: PubMed Scopus Google Scholar). Several recent studies that SPNS2 also be involved in these of SPNS2 in cell cells increased S1P secretion but also led to increased and decreased cell SPNS2 was in a of human E. S. G. Q. M. E. G. role of Spns2, a sphingosine-1-phosphate transporter, in cancer cell and 2014; PubMed Scopus Google Scholar). could be by the of these cancer cells for S1P signaling, signaling through S1PRs, or SPNS2 was required for growth and in endothelial cells P. M. A. of sphingosine kinase 1 and S1P transporter in in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This was on SphK1 the of S1P, and extracellular transport of S1P and its inside-out signaling P. M. A. of sphingosine kinase 1 and S1P transporter in in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). SPNS2 was with increased of cells M.M. D. N. M. M.J. J.C. sphingosine kinase sphingosine-1-phosphate epidermal growth phosphorylation and cancer cell J. 2015; PubMed Scopus Google Scholar). This also showed that signaling through S1PR2 to However, in a on the inside-out S1P signaling this could not be blocked by an extracellular S1P suggesting a novel intracellular for SPNS2 to S1P into an intracellular such as leading to the activation of S1PR2 M.M. D. N. M. M.J. J.C. sphingosine kinase sphingosine-1-phosphate epidermal growth phosphorylation and cancer cell J. 2015; PubMed Scopus Google Scholar). in the signaling the and SPNS2 was required for it was not this was due to S1P G. A. S. M. J. T. K. M. Cuvillier O. et al.Sphingosine 1-phosphate signaling through its receptor and Signal. 10: PubMed Scopus Google Scholar). In contrast, the S1P was to the factor signaling in cells P. C. D. J. L. S. Y. et role for signaling to regulate factor expression and in PubMed Scopus Google Scholar). is some evidence that a role for SPNS2 in cancer cells the importance of SPNS2 in was by a of knockout mice for that regulate to of the L. M.J. T. H. N. T. et in novel of PubMed Scopus Google Scholar). This involved cells into the of knockout mice and their and then the of the of was the knockout of the SPNS2 gene L. M.J. T. H. N. T. et in novel of PubMed Scopus Google Scholar). The of was not due to a in the ability of the cancer cells to the but of the cancer cells in the indicating a in the knockout The of SPNS2, or in a lymphatic endothelial first it that in the However, it was demonstrated that a in the of to was and also was an in cells in the of mice (Fig. In and from SPNS2 knockout had in studies demonstrated that and cells to the This a novel for the role of tissue in cancer and that SPNS2 could be an for after by the of to the cancer cells. epidermal growth factor major facility superfamily sphingosine-1-phosphate S1P receptor sphingosine kinase spinster homologue 2