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

Abstract

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