Functions of the Multifaceted Family of Sphingosine Kinases and Some Close Relatives

Sphingosine kinases (SphK) 3The abbreviations used are: SphK, sphingosine kinase; S1P, sphingosine 1-phosphate; C1P, ceramide 1-phosphate; CerK, ceramide kinase; AGK, acylglycerol kinase; PLA2, phospholipase A2; EGFR, epidermal growth factor receptor; LPA, lysophosphatidic acid; PA, phosphatidic acid. are prototypical members of a highly conserved family of signaling enzymes. They are present in organisms as diverse as mammals, flies, worms, yeast, and plants and catalyze the phosphorylation of sphingosine to form the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P). Two distinct mammalian isoforms have been identified, SphK1 and SphK2. Other close relatives, ceramide kinase (CerK) and the more promiscuous acylglycerol kinase (AGK), are now emerging as lipid-signaling kinases with important functions. This brief review will focus on the biochemical properties of this novel family of lipid kinases with emphasis on recent studies that have begun to uncover the biological functions of their phosphorylated products. As a specific ligand for a family of five G protein-coupled receptors, termed S1P1–5, S1P regulates diverse physiological processes important for cancer as well as lymphocyte trafficking, immunity, and allergy. S1P also has receptor-independent intracellular functions in mammalian cells important for calcium homeostasis, cell growth, and suppression of apoptosis (reviewed in Ref. 1Spiegel S. Milstien S. Nat. Rev. Mol. Cell Biol. 2003; 4: 397-407Crossref PubMed Scopus (1758) Google Scholar), consistent with the observations that lower organisms, including plants and yeast, although they express sphingosine kinases and produce and respond to S1P, do not express S1P receptors. Interest in the functions of S1P in the immune system has increased recently due to the discovery that the potent immunosuppressive drug FTY720, a sphingosine analogue, has great clinical potential for the prevention of renal graft rejection (2Tedesco-Silva H. Mourad G. Kahan B.D. Boira J.G. Weimar W. Mulgaonkar S. Nashan B. Madsen S. Charpentier B. Pellet P. Vanrenterghem Y. Transplantation. 2005; 79: 1553-1560Crossref PubMed Scopus (212) Google Scholar) and treatment of multiple sclerosis where it is currently in phase II clinical trials (3Kappos L. Antel J. Comi G. Montalban X. O'Connor P. Polman C.H. Haas T. Korn A.A. Karlsson G. Radue E.W. N. Engl. J. Med. 2006; 355: 1124-1140Crossref PubMed Scopus (946) Google Scholar). A large body of evidence suggests that FTY720 is a pro-drug that is phosphorylated by SphK2 to a mimetic of S1P, FTY720-P, which prevents egress of T-cells from secondary lymphoid organs and back into circulation by functionally antagonizing S1P1 (4Cyster J.G. Annu. Rev. Immunol. 2005; 23: 127-159Crossref PubMed Scopus (719) Google Scholar, 5Rosen H. Goetzl E.J. Nat. Rev. Immunol. 2005; 5: 560-570Crossref PubMed Scopus (621) Google Scholar). Fascinatingly, Kruppel-like factor 2, a transcription factor known to influence T-cell survival, regulates thymocyte and T-cell trafficking by binding and transactivating the promoter for S1P1 to enhance its expression (6Carlson C.M. Endrizzi B.T. Wu J. Ding X. Weinreich M.A. Walsh E.R. Wani M.A. Lingrel J.B. Hogquist K.A. Jameson S.C. Nature. 2006; 442: 299-302Crossref PubMed Scopus (422) Google Scholar). In addition, it has also been demonstrated that agonists can act through S1P1 on endothelial cells to enhance adherens junction and endothelial barrier function to prevent lymphocyte egress from lymph nodes (7Sanna M.G. Wang S.K. Gonzalez-Cabrera P.J. Don A. Marsolais D. Matheu M.P. Wei S.H. Parker I. Jo E. Cheng W.C. Cahalan M.D. Wong C.H. Rosen H. Nat. Chem. Biol. 2006; 2: 434-441Crossref PubMed Scopus (343) Google Scholar). S1P may also be important for arrival of mast cells (8Jolly P.S. Bektas M. Olivera A. Gonzalez-Espinosa C. Proia R.L. Rivera J. Milstien S. Spiegel S. J. Exp. Med. 2004; 199: 959-970Crossref PubMed Scopus (290) Google Scholar) and eosinophils (9Roviezzo F. Del Galdo F. Abbate G. Bucci M. D'Agostino B. Antunes E. Dominicis G.De Parente L. Rossi F. Cirino G. De Palma R. Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 11170-11175Crossref PubMed Scopus (88) Google Scholar) to sites of inflammation. In an animal asthma model, FTY720 inhibited the infiltration of both Th2 cells and eosinophils into bronchial tissue, reduced the levels of Th2-related cytokines, and almost completely blocked airway hyper-responsiveness (10Idzko M. Hammad H. van Nimwegen M. Kool M. Muller T. Soullie T. Willart M.A. Hijdra D. Hoogsteden H.C. Lambrecht B.N. J. Clin. Invest. 2006; 116: 2935-2944Crossref PubMed Scopus (229) Google Scholar), all characteristic features of clinical asthma. Interestingly, it was recently found that unphosphorylated FTY720 blocked stimulated secretion of all eicosanoids from mast cells and macrophages by directly inhibiting cytosolic PLA2, the rate-limiting step in eicosanoid formation, independently of S1P receptor functions (11Payne S.G. Oskeritzian C.A. Griffiths R. Subramanian P. Barbour S.E. Chalfant C.E. Milstien S. Spiegel S. Blood,. 2006; (in press)PubMed Google Scholar). These findings have important implications for the potential therapeutic mechanism of action of this potent immunosuppressive drug in inflammatory and allergic responses. Many reports have shown that S1P is an important player in the regulation of cancer cell survival and tumor progression. Growth factors, hormones important for progression of cancer, and cytokines stimulate SphK1 and production of S1P (1Spiegel S. Milstien S. Nat. Rev. Mol. Cell Biol. 2003; 4: 397-407Crossref PubMed Scopus (1758) Google Scholar). SphK1 is a critical regulator of the balance between the pro-growth and anti-apoptotic S1P and its pro-apoptotic precursors ceramide and sphingosine. Numerous previous studies have shown that overexpression of SphK1 promotes tumorigenesis (12Milstien S. Spiegel S. Cancer Cell. 2006; 9: 148-150Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). In accordance, down-regulating its expression in cancer cells reduces growth, increases apoptosis, and enhances chemosensitivity (13Taha T.A. Kitatani K. El-Alwani M. Bielawski J. Hannun Y.A. Obeid L.M. FASEB J. 2006; 20: 482-484Crossref PubMed Scopus (128) Google Scholar). Recently it was suggested that SphK1 regulates autophagy, a normal physiologic self-digestion mechanism for the turnover of cellular proteins and excess or damaged organelles, to protect cancer cells from apoptosis during nutrient starvation (14Lavieu G. Scarlatti F. Sala G. Carpentier S. Levade T. Ghidoni R. Botti J. Codogno P. J. Biol. Chem. 2006; 281: 8518-8527Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar). Moreover, SphK1 is up-regulated in a variety of solid tumors, including breast, colon, lung, ovary, stomach, uterus, kidney, and rectum (15French K.J. Schrecengost R.S. Lee B.D. Zhuang Y. Smith S.N. Eberly J.L. Yun J.K. Smith C.D. Cancer Res. 2003; 63: 5962-5969PubMed Google Scholar), and several lipid and non-lipid SphK inhibitors have anti-tumor activity in xenograft models (16French K.J. Upson J.J. Keller S.N. Zhuang Y. Yun J.K. Smith C.D. J. Pharmacol. Exp. Ther. 2006; 318: 596-603Crossref PubMed Scopus (219) Google Scholar). An elegant study recently demonstrated that intravenous administration of a monoclonal antibody that neutralizes S1P drastically reduced tumor progression and associated angiogenesis in several animal models of human cancer (17Visentin B. Vekich J.A. Sibbald B.J. Cavalli A.L. Moreno K.M. Matteo R.G. Garland W.A. Lu Y. Yu S. Hall H.S. Kundra V. Mills G.B. Sabbadini R.A. Cancer Cell. 2006; 9: 225-238Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). These results suggest that S1P not only has effects on tumor cells themselves but also is permissive or required for the actions of angiogenic factors and provide proof of concept that targeting of this important sphingolipid signaling molecule is a novel strategy for the development of new types of cancer treatments. Transactivation of growth factor receptor tyrosine kinases by G protein-coupled receptor ligands, such as S1P, is important for amplification of signaling and regulation of cell growth. A reciprocal mechanism of receptor cross-talk has been shown to regulate movement of cells whereby activation of receptor tyrosine kinases stimulates and translocates SphK1 to the plasma membrane, resulting in spatially restricted formation of S1P that in turn activates S1P1 (or other S1P receptors present on the cell surface) and downstream signaling events critical for directed cell movement (Fig. 1) (18Hobson J.P. Rosenfeldt H.M. Barak L.S. Olivera A. Poulton S. Caron M.G. Milstien S. Spiegel S. Science. 2001; 291: 1800-1803Crossref PubMed Scopus (384) Google Scholar). Thus, S1P might be the central controller of several amplification loops, in line with the emerging view of the intricacy and nonlinearity of signaling via S1P receptors and receptor tyrosine kinases and the importance of membrane compartmentalization of a signaling complex (signalplex). This web has become even more entangled by the recent demonstration that estrogen acting on its own receptors stimulates SphK1 and the release of S1P, which in turn activates S1P3 leading to EGFR transactivation in a matrix metalloprotease-dependent manner (19Sukocheva O. Wadham C. Holmes A. Albanese N. Verrier E. Feng F. Bernal A. Derian C.K. Ullrich A. Vadas M.A. Xia P. J. Cell Biol. 2006; 173: 301-310Crossref PubMed Scopus (186) Google Scholar). It is still a mystery how S1P produced inside cells by two SphKs can reach its receptors on the cell surface. Although it has been suggested that extracellular production of S1P by exported SphK1 may contribute to the establishment of the vascular S1P gradient (20Venkataraman K. Thangada S. Michaud J. Oo M.L. Ai Y. Lee Y.M. Wu M. Parikh N.S. Khan F. Proia R.L. Hla T. Biochem. J. 2006; 397: 461-471Crossref PubMed Scopus (173) Google Scholar), data from many studies indicate that intracellularly produced S1P itself is secreted. Studies originally related to multidrug resistance in cancer cells identified several ATP-binding cassette (ABC) transporters, including ABCB1 (previously called MDR-1 and P-glycoprotein) and ABCC1 (previously called MRP1) that, in addition to export of amphiphilic drugs, catalyze the movement of lipids from the inner to the outer leaflet of the plasma membrane. It is well documented that many ABC transporters are up-regulated in solid and hematological cancers, and in some cases, their expression correlates with negative responses to treatment and poor disease outcome. The ability of S1P to act in an autocrine or paracrine manner to regulate angiogenesis and vascular maturation suggests that increased secretion of S1P by cancer cells, perhaps by ABC transporters, due to up-regulation of SphK1 or the transporters, could contribute to tumorigenesis. Curiously, both ABCB1 and ABCC1 are required for FTY720 to induce lymphocyte homing (21Honig S.M. Fu S. Mao X. Yopp A. Gunn M.D. Randolph G.J. Bromberg J.S. J. Clin. Invest. 2003; 111: 627-637Crossref PubMed Scopus (121) Google Scholar). Recent work suggests that ABCC1 is also responsible for transport of S1P, as its down-regulation as well as a specific inhibitor decreased secretion of S1P from human and rodent mast cells (22Mitra P. Oskeritzian C.A. Payne S.G. Beaven M.A. Milstien S. Spiegel S. Proc. Natl. Acad. Sci. U. S. A. 2006; 44: 16394-16399Crossref Scopus (348) Google Scholar). Activation and translocation of both isoforms of SphK to the plasma membrane after FcϵRI cross-linking and therefore to their substrate sphingosine (23Olivera A. Urtz N. Mizugishi K. Yamashita Y. Gilfillan A.M. Furumoto Y. Gu H. Proia R.L. Baumruker T. Rivera J. J. Biol. Chem. 2006; 281: 2515-2525Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar) and the subsequent synthesis of S1P at the plasma membrane in close proximity to ABCC1 could account for the abundant and stimulated secretion of S1P by antigen in mast cells (Fig. 1). These findings have important implications for intracellular and extracellular functions of S1P in mast cell-mediated immune responses. It will be important to determine whether S1P release from other cells, particularly cancer cells, is also mediated by ABC transporters. The ubiquitously expressed SphK2 also has the same five evolutionarily conserved domains found in all SphKs (Fig. 2) but diverges in its central region and has a longer amino terminus. SphK1 and SphK2 have different kinetic properties and also have different developmental and tissue expression patterns, suggesting that they have distinct physiological functions. Little is known of the functions of SphK2, although its overexpression suppresses cell growth and enhances apoptosis (24Liu H. Toman R.E. Goparaju S. Maceyka M. Nava V.E. Sankala H. Payne S.G. Bektas M. Ishii I. Chun J. Milstien S. Spiegel S. J. Biol. Chem. 2003; 278: 40330-40336Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). These effects of SphK2 might be related to its to the T. Ding G. H. T. Y. A. S. N. S. S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) or M. Sankala H. H. Toman R. C. M. L. Milstien S. Spiegel S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) or to its (24Liu H. Toman R.E. Goparaju S. Maceyka M. Nava V.E. Sankala H. Payne S.G. Bektas M. Ishii I. Chun J. Milstien S. Spiegel S. J. Biol. Chem. 2003; 278: 40330-40336Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). the of SphK2 is still as down-regulating its expression growth and apoptosis of cells C.A. P.J. J. Exp. 2005; PubMed Scopus Google Scholar) cells from apoptosis T. Ding G. H. T. Y. A. S. N. S. S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). expression of SphK2 increased production of SphK1 decreased it M. Sankala H. H. Toman R. C. M. L. Milstien S. Spiegel S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In accordance, down-regulating SphK2 reduced of sphingosine to ceramide in the and down-regulating SphK1 increased it (13Taha T.A. Kitatani K. El-Alwani M. Bielawski J. Hannun Y.A. Obeid L.M. FASEB J. 2006; 20: 482-484Crossref PubMed Scopus (128) Google Scholar, M. Sankala H. H. Toman R. C. M. L. Milstien S. Spiegel S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). do SphK1 and SphK2 effects on ceramide Sphingosine is not produced by it is from of ceramide by and can be for ceramide and complex sphingolipid synthesis or phosphorylated by SphKs to form Thus, SphK2 might a in a sphingosine of mammalian cells, acting in with S1P to S1P back to sphingosine and to In S1P by SphK1 may ceramide as a cellular mechanism to regulate levels of ceramide M. Sankala H. H. Toman R. C. M. L. Milstien S. Spiegel S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The two SphK might also have some functions. both SphK1 and SphK2 required for of cancer cells but not for of cells S. H. A. Maceyka M. Milstien S. Spiegel S. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). although the have the is with including and by a in apoptosis and a in in the system K. Yamashita T. Olivera A. Spiegel S. Proia R.L. Mol. Cell. 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