1 Department of Biochemistry, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA
2 Research and Development, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249, USA
* Author for correspondence (e-mail: cechalfant{at}vcu.edu)
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Summary |
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Key words: Ceramide 1-phosphate, Ceramide kinase, Sphingosine 1-phosphate, Sphingosine kinase, Inflammation, Cancer
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Introduction |
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The interconvertible ceramide-derived metabolites S1P and C1P, also represent an important class of bioactive lipid mediators. There are two mammalian SphK isoenzymes, SphK1 and SphK2, which catalyze the phosphorylation of sphingosine to S1P (Spiegel and Milstien, 2003). Although sphingosine may also be an important physiological regulator, because it can inhibit protein kinase C as well as induce cell-cycle arrest and apoptosis, S1P has distinct roles in cell growth and survival, angiogenesis, vasculogenesis, neuritogenesis, and immune function, and the number of reports on S1P-mediated cell signaling has exploded in recent years (Spiegel and Milstien, 2003
). Extracellular actions of S1P are mediated by its interaction with a family of five specific G-protein-coupled receptors (GPCRs), S1P1-S1P5 (Goetzl and Rosen, 2004
; Spiegel and Milstien, 2003
). In addition, similarly to other potent lipid mediators, S1P also has intracellular actions independent of these receptors (Spiegel and Milstien, 2003
).
C1P is another phosphorylated bioactive sphingolipid whose importance has only recently begun to be appreciated. Although C1P was identified more than a decade ago, tantalizing hints of its potential biological functions have only appeared in the last few years (Liang et al., 2003; Pettus et al., 2003a
). C1P was originally detected in HL-60 human leukemia cells, where it was shown to be formed by phosphorylation of sphingomyelin-derived ceramide by a kinase that was functionally and physically separable from diacylglycerol kinase (Kolesnick and Hemer, 1990
). CERK is now known to be a distinct but close relative of SphKs that catalyzes the phosphorylation of ceramide to give C1P (Sugiura et al., 2002
), and its cloning has helped to uncover new physiological functions for C1P. Here, we focus on the emerging roles of S1P and C1P in inflammatory responses and touch on recent insights into their mechanisms of action, and their functions in plants.
Functions of S1P in cell migration and lymphocyte trafficking
Diverse external stimuli, including PDGF, VEGF and TNF- (reviewed in Spiegel and Milstien, 2003
), stimulate SphK1 to generate intracellular S1P, which can function in an autocrine or paracrine fashion to activate S1P receptors present on the surface of the same or a nearby cell. This type of signaling is important for migration of cells towards PDGF and has important implications for vascular maturation. Activation of the S1P1 receptor stimulates downstream signals important for cell locomotion (Hobson et al., 2001
; Rosenfeldt et al., 2001
), whereas S1P2 acts to dampen this. Thus the net responses to S1P depend on the relative expression levels of these two receptors and their activation in response to PDGF (Goparaju et al., 2005
).
Interest in the functions of S1P in the immune system has increased recently owing to the discovery that the potent immunosuppressive drug FTY720, which is now in clinical trials for kidney transplantation and multiple sclerosis, is a sphingosine analogue that is phosphorylated by SphK2 and functions as a S1P mimetic to induce sequestration of T lymphocytes in thymus and lymph nodes (Brinkmann et al., 2002; Cyster, 2005
; Goetzl and Graler, 2004
; Mandala et al., 2002
). Adaptive immunity depends on circulation of T and B cells between secondary lymphoid organs to monitor antigens. Studies with mice, whose hematopoietic cells lack S1P1, have established that this S1P receptor is essential for lymphocyte recirculation and tissue homing (Matloubian et al., 2004
). Although it is not completely understood how S1P gradients regulate lymphocyte trafficking, it has been suggested that low concentrations of S1P (between 10 and 100 nM) are optimal for enhancing chemotaxis of lymphocytes to chemokines and some cytokines (Graeler and Goetzl, 2002
; Rosen and Goetzl, 2005
). By contrast, the higher concentrations of S1P (100 to 1000 nM) in the blood inhibit chemokine-induced movement of T cells from high endothelial venules into secondary lymphoid organs (Rosen and Goetzl, 2005
). Several studies suggest that the chemotactic responsiveness of T cells to S1P increases between the time of entry into and exit from secondary lymphoid organs (Lo et al., 2005
). However, the mechanisms that regulate S1P1 expression and signaling are unknown. Although much remains to be learned, it is clear that S1P, acting through S1P1, is a major regulator of T-cell development, B- and T-cell recirculation, lymphocyte homing and chemotactic responses to chemokines (Goetzl and Rosen, 2004
). This pattern of lymphocyte responses suggests that, new forms of immunotherapy that specifically target this S1P receptor on immune cells might be uniquely valuable for suppression of organ-graft rejection without impairment of host defences against infections.
C1P and S1P in inflammatory responses
Eicosanoids (e.g. prostaglandins and leukotrienes) are well-established mediators of inflammatory responses with roles in the pathogenesis of cancer and inflammatory disorders such as atherosclerosis, asthma, osteoarthritis and Alzeimer's disease. The formation of arachidonic acid (AA) via the activation of phospholipase A2 is the initial rate-limiting step in eicosanoid biosynthesis (Clark et al., 1995). In many cases, inflammatory agonists induce activation and translocation of group IVA cytosolic phospholipase A2 (cPLA2
) in a Ca2+-dependent or -independent manner, a process whose mechanism and mediators have not been completely elucidated (Scott et al., 1999
). Depending on the basal levels of expression of downstream enzymes in the eicosanoid pathway for example, cyclooxygenase 2 (COX-2) their transcription (if necessary and this varies by cell type) can be induced in a secondary rate-limiting step (Scott et al., 1999
). Increased COX-2 synthesis in most cases occurs prior to cPLA2
activation and is termed `priming' the system for optimal response. COX-2 then utilizes the AA released by cPLA2 to initiate the prostaglandin-synthesis pathways (Scott et al., 1999
). In the leukotriene pathway, the initial enzyme, lipoxygenase (LO), also utilizes AA as a substrate.
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Since ceramide, C1P, sphingosine and S1P are interconvertible, they might function as components of a `rheostat' that regulates immune cell functions, including mast cell responsiveness, neutrophil and macrophage priming, chemotaxis, and survival of many types of immune cells (Goetzl and Rosen, 2004; Olivera and Rivera, 2005
; Spiegel and Milstien, 2003
). Activation of SphK1 by a variety of cytokines and concomitant formation of S1P are important for various inflammatory responses (Goetzl and Rosen, 2004
; Olivera and Rivera, 2005
; Spiegel and Milstien, 2003
). A recent study showed that ceramide, sphingosine, and S1P can all induce COX-2 in A549 human lung cells and macrophages (Pettus et al., 2003b
) but S1P is the most potent. In response to TNF-
treatment, there is a significant increase in the levels of S1P, and downregulation of SphK1, but not SphK2, blocks this, as well as PGE2 production. Conversely, RNAi directed against S1P lyase or S1P phosphatase, which should increase S1P levels, enhances TNF-induced COX-2 and PGE2 production. Importantly, expression of SphK1 is necessary for the induction of COX-2 by ceramide and sphingosine, but not S1P, indicating that these two sphingolipid metabolites act through their conversion to S1P (Fig. 2).
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Mast cells are also important players in inflammatory responses, and S1P and C1P are also thought to regulate many of their functions, including degranulation and chemotaxis (Jolly et al., 2004; Jolly et al., 2005
). Cross-linking of the high-affinity receptor for IgE (Fc
RI) on mast cells activates SphK1, leading to generation and secretion of S1P, which in turn activates its receptors S1P1 and S1P2 on mast cells. Although activation of S1P1 and Gi signaling are important for cytoskeletal rearrangements and migration of mast cells towards antigen, they are dispensable for Fc
RI-triggered degranulation (Jolly et al., 2004
). However, S1P2, whose expression is upregulated by Fc
RI cross-linking, is required for degranulation. Furthermore, RNAi directed against SphK1 and SphK2 clearly showed that SphK1 and S1P are required for degranulation of mast cells (Jolly et al., 2004
). Activation of SphK1 and, consequently, S1P receptors by Fc
RI triggering thus seems to play a crucial role in mast cell functions and might be involved both in the movement of these cells to sites of inflammation and in their degranulation.
CERK and its product, C1P, could also function in degranulation of mast cells because overexpression of CERK enhances degranulation of RBL-2H3 cells induced by A23187 (Mitsutake et al., 2004). However, the interconversion of C1P with the other bioactive sphingolipid metabolites was not considered in this study, and it is possible that overexpression of CERK or treatment of cells with C1P merely influences the levels of S1P. Establishing whether S1P and C1P have non-overlapping roles in this case therefore warrants more comprehensive studies (Fig. 3).
cPLA2 as a target of C1P
Unlike S1P, C1P is not thought to act through a cell surface receptor. It probably functions instead at the intracellular level. cPLA2 is an obvious potential target and recent work supports the idea that C1P regulates this enzyme by direct interactions (Pettus et al., 2003a
). cPLA2
has a calcium-dependent lipid-binding (C2/CaLB) domain similar to the C2 domain of protein kinase C (PKC) (Clark et al., 1991
). C1P, an anionic lipid, might therefore interact directly with this domain in a fashion analogous to that by which phosphatidylserine interacts with the C2 domain of PKC. Alternatively, C1P could also indirectly activate cPLA2
since exogenous C1P has been reported to induce calcium mobilization (Tornquist et al., 2004
). We have recently discovered that C1P is indeed a direct activator of cPLA2
that interacts with its C2/CaLB domain (Subramanian et al., 2005
). This was a somewhat unexpected finding because the current dogma is that zwitterionic lipids, such as phosphatidylcholine, rather than anionic lipids such as C1P, bind to the C2/CaLB domain (Hixon et al., 1998
). Nevertheless, there is significant interaction between C1P and cPLA2
or its C2/CaLB domain at 300 nM calcium (Subramanian et al., 2005
), which is in agreement with early findings suggesting that association of cPLA2 with membranes requires 300 nM calcium (Clark et al., 1991
).
Importantly, C1P specifically activates cPLA2, both by an allosteric mechanism and by lowering the dissociation constant of the enzyme for phosphatidylcholine-rich vesicles (Subramanian et al., 2005
). Given the latter effect, C1P could be involved in the recruitment of cPLA2
to the Golgi complex. CERK localizes to the Golgi complex in HUVECs, COS-1 and A549 cells (Carre et al., 2004
) (our unpublished findings), and C1P can thus be generated in the appropriate cellular compartment for recruitment of cPLA2
in response to inflammatory agonists. Recent work indicates that C1P interacts with a novel site within the C2/CaLB domain [near calcium binding region II (CBR II) of cPLA2
] and does not compete with the interaction sites for phosphatidylcholine (CBRI and CBRIII) or PtdIns(4,5,)P2 (the catalytic domain) (Subramanian et al., 2005
).
Regulation of cell survival by C1P and S1P
Other possible direct targets of C1P are protein phosphatase 1 and protein phosphatase 2A (PP1 and PP2A). Ceramide is an activator of these serine/threonine protein phosphatases (also known as CAPPs), which have been linked to ceramide-induced apoptosis (Chalfant et al., 2002). Activation of PP1 by ceramide leads to dephosphorylation of SR proteins, a family of serine/arginine-domain proteins that modulate mRNA splicing, reducing the levels of the anti-apoptotic protein Bcl-x(L) and increasing the levels of apoptotic Bcl-x(S). Interestingly, C1P is a potent inhibitor (IC50 50 nM) of both PP1 and PP2A in vitro (Chalfant, 2004
). This observation ties in well with the mitogenic/survival effects of C1P, because inhibition of these phosphatases has been linked to activation of the ERK1/2 pathway and increased DNA synthesis (Dougherty et al., 2005
; Hancock et al., 2005
).
This potential of C1P to function as an inhibitory signaling molecule regulating PP1 activity is also directly relevant to the role of alternative splicing in cancer. Chemotherapeutic agents induce a pro-apoptotic change in the alternative splicing of caspase 9 and Bcl-x pre-mRNA (Massiello et al., 2004). This effect is mediated by ceramide-dependent activation of PP1 (Massiello et al., 2004
). Since C1P is a potent inhibitor of PP1, one can hypothesize that C1P generated by CERK antagonises ceramide action (e.g. activation of PP1 and subsequent effects on Bcl-x and caspase-9 alternative splicing) and is thus pro-survival and cytoprotective. This idea has also been recently alluded to by Gomez-Munoz and co-workers, who demonstrated that C1P induces the expression of Bcl-x(L) and cell survival (Gomez-Munoz et al., 2005
). Unfortunately, they did not examine the expression of Bcl-x(S). If indeed Bcl-x(L) levels do increase at the expense of Bcl-x(S), then CERK may be a crucial switch that regulates the fate of a cell in response to apoptotic agonists by having opposite effects on the alternative splicing of Bcl-x and caspase 9 pre-mRNA. By analogy with SphK1, which converts pro-apoptotic sphingosine to anti-apoptotic S1P, CERK may also play a homeostatic role regulating the balance between ceramide and C1P. Therefore, SphK1 and CERK may both be key determinants of the balance between cell death and cell survival (Fig. 1).
Intracellular targets for S1P
As previously mentioned, S1P acts through cell surface receptors but might also have direct intracellular targets. Several crucial studies have clearly shown that, S1P has specific intracellular actions that are independent of its cell surface receptors. For example, activation of Ras and ERK signaling pathways by VEGF requires SphK1 and is independent of S1P receptors (Shu et al., 2002; Wu et al., 2003
), in contrast to cytoskeletal rearrangements and cell locomotion (Olivera et al., 2003
). Similarly, TNF-
stimulates SphK1, leading to the activation of the transcription factor nuclear factor NF-
B, which is essential for the prevention of apoptosis (Xia et al., 2002
). In addition, S1P inhibits male germ cell apoptosis independently of its receptors, possibly by inhibiting NF-
B and Akt phosphorylation (Suomalainen et al., 2005
). SphK1 also enhances endothelial cell survival through PECAM-1-dependent activation of PI3K/Akt and regulation of Bcl-2 family members, without activating S1P receptors or ERK signaling (Limaye et al., 2005
). Moreover, S1P can induce calcium mobilization independently of GPCRs (Meyer zu Heringdorf et al., 2003
). Lastly, numerous studies in plants (see below), yeast, Dictyostelium, Drosophila and Caenorhabditis elegans revealed that S1P has important regulatory functions in these diverse lower organisms, which are devoid of S1P receptors (Herr et al., 2004
; Herr et al., 2003
; Min et al., 2005
). Degradation of S1P by S1P lyase in Drosophila, for example, regulates the flux of sphingolipid metabolites into phospholipid synthesis and controls the release of sterol-regulatory-element-binding protein (SREBP) from cell membranes, as a feedback-control mechanism regulating synthesis of fatty acids and phospholipids (Dobrosotskaya et al., 2002
). Clearly, an important missing piece of the intracellular S1P signaling puzzle is the identification of direct intracellular targets.
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Recent studies suggest that SphK and S1P also have important functions linking the perception of abscisic acid (ABA) to reductions in guard-cell turgor (Ng et al., 2001). The drought hormone ABA activates SphK in A. thaliana and the S1P formed is involved in both inhibition of stomatal opening and promotion of stomatal closure (Coursol et al., 2003
). Inhibition of SphK attenuates ABA-mediated regulation of guard-cell inwardly rectifying K+ channels and slow anion-channels, which are involved in the regulation of stomatal pore size (Coursol et al., 2003
). The action of S1P is impaired in A. thaliana knockout lines that lack the sole prototypical G protein
subunit GPA1, which indicates that heterotrimeric G proteins are downstream targets for S1P.
Notice that, whereas in mammals the prevalent long-chain base is sphingosine, which has a chain length of 18 carbon atoms and an E-double bond between C4 and C5, in plants the predominant long-chain bases are dihydrosphingosine and phytosphingosine, a saturated and 4-hydroxylated form of dihydrosphingosine (Fig. 4B). In common with S1P, phyto-S1P inhibits stomatal opening and promotes stomatal closure in A. thaliana, and these actions are also impaired in guard cells of GPA1-knockout plants.
Importantly, these effects of S1P are unlikely to be mediated by a GPCR because guard cells lacking the only A. thaliana GPCR-like protein, GCR1, have responses to ABA and S1P opposite to those of GPA1 mutants (Pandey and Assmann, 2004). Moreover, GCR1 has no significant sequence similarity to any of the conserved S1P receptors and does not bind either S1P or phyto-S1P. Therefore, the S1P signal in guard cells may be transduced by a direct interaction between S1P and GPA1 (Fig. 4A). Alternatively, S1P might act through an unidentified intermediate similar to AGS (activator of G protein signaling) a protein that can activate heterotrimeric G proteins independently of GPCRs (Cismowski et al., 2001
; Vaidyanathan et al., 2004
).
Interestingly, GPA1 regulates not only guard-cell function but also plant cell division (Ullah et al., 2001). The discovery that it is a downstream component of S1P and phyto-S1P signaling in guard cells raises the exciting possibility that phosphorylated sphingoid bases play a role in other G-protein-mediated processes in plants, particularly those related to cell proliferation. Moreover, this might help to reveal the enigmatic intracellular actions of S1P in mammals. Future work, therefore, will probably reveal novel mechanisms of S1P signaling through G proteins in diverse eukaryotes.
Perspectives
Because of the strong association between chronic inflammation and cancer (Lawrence et al., 2005; Nakanishi and Toi, 2005
), coordinate regulation of inflammatory responses to cytokines by C1P and S1P suggests they may be ideal pharmacological targets for development of novel anti-inflammatory and anti-cancer therapies. The development of such drugs could be of key importance in light of the recent reports on the side effects of COX-2 inhibitors, such as VIOXX. The cause of these side-effects is unknown, but several possibilities exist. First, a COX-2 inhibitor might have non-specific cellular targets, and thus long-term administration could dysregulate important signaling pathways required for proper cell maintenance. Second, some basal level of prostaglandins synthesized by COX-2 may be required for normal homeostasis. Third, abnormal eicosanoids could be produced from excess AA, resulting from its lack of use by inhibited COX-2. Specific SphK1 inhibitors would clearly not have the same non-specific effects as COX-2 inhibitors. Moreover, CERK inhibition in conjunction with SphK1 inhibition or possibly even with VIOXX or Bextra might overcome the third possibility through their negative effects on cPLA2, decreasing availability of AA. If specific eiconsanoids produced by basal level COX-2 activity are important for normal cell functions, this would clearly be the most difficult problem to overcome. Inhibition of CERK to block inflammatory responses could potentially be as useful as COX-2 inhibitors were hoped to be. Since other eicosanoids, such as leukotrienes and thromboxanes, also regulate inflammatory responses, CERK inhibitors could have the added benefit of blocking all eicosanoid synthesis by inhibiting AA release in response to inflammatory mediators.
C1P and S1P have been shown to regulate important cellular processes in plants as well as mammals, demonstrating the broad and important role for these lipids in cell signaling cascades conserved across evolution. We hope that recent exciting and provocative results discussed here will stimulate the scientific community to undertake the daunting tasks of identifying intracellular targets for C1P and S1P and developing clinically useful therapies based on this knowledge.
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Acknowledgments |
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References |
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Brinkmann, V., Davis, M. D., Heise, C. E., Albert, R., Cottens, S., Hof, R., Bruns, C., Prieschl, E., Baumruker, T., Hiestand, P. et al. (2002). The immune modulator, FTY720, targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453-21457.
Carre, A., Graf, C., Stora, S., Mechtcheriakova, D., Csonga, R., Urtz, N., Billich, A., Baumruker, T. and Bornancin, F. (2004). Ceramide kinase targeting and activity determined by its N-terminal pleckstrin homology domain. Biochem. Biophys. Res. Commun. 324, 1215-1219.[CrossRef][Medline]
Chalfant, C. E. (2004). Ceramide Kinase. In Lipids: Sphingolipid Metabolizing Enzymes (eds D. Haldar and K. S. Das), pp. 17-31. Kerala, India: Research Signpost.
Chalfant, C. E., Rathman, K., Pinkerman, R. L., Wood, R. E., Obeid, L. M., Ogretmen, B. and Hannun, Y. A. (2002). De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J. Biol. Chem. 277, 12587-12595.
Cismowski, M. J., Takesono, A., Bernard, M. L., Duzic, E. and Lanier, S. M. (2001). Receptor-independent activators of heterotrimeric G-proteins. Life Sci. 68, 2301-2308.[CrossRef][Medline]
Clark, J. D., Lin, L. L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N. and Knopf, J. L. (1991). A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051.[CrossRef][Medline]
Clark, J. D., Schievella, A. R., Nalefski, E. A. and Lin, L. L. (1995). Cytosolic phospholipase A2. J. Lipid Mediat. Cell Signal. 12, 83-117.[CrossRef][Medline]
Coursol, S., Fan, L. M., Le Stunff, H., Spiegel, S., Gilroy, S. and Assmann, S. M. (2003). Sphingolipid signalling in Arabidopsis guard cells involves heterotrimeric G proteins. Nature 423, 651-654.[CrossRef][Medline]
Cyster, J. G. (2005). Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127-159.[CrossRef][Medline]
Dobrosotskaya, I. Y., Seegmiller, A. C., Brown, M. S., Goldstein, J. L. and Rawson, R. B. (2002). Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila. Science 296, 879-883.
Dougherty, M. K., Muller, J., Ritt, D. A., Zhou, M., Zhou, X. Z., Copeland, T. D., Conrads, T. P., Veenstra, T. D., Lu, K. P. and Morrison, D. K. (2005). Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215-224.[CrossRef][Medline]
Futerman, A. H. and Hannun, Y. A. (2004). The complex life of simple sphingolipids. EMBO Rep. 5, 777-782.
Goetzl, E. J. and Graler, M. H. (2004). Sphingosine 1-phosphate and its type 1 G protein-coupled receptor: trophic support and functional regulation of T Lymphocytes. J. Leukoc. Biol. 76, 30-35.
Goetzl, E. J. and Rosen, H. (2004). Regulation of immunity by lysosphingolipids and their G protein-coupled receptors. J. Clin. Invest. 114, 1531-1537.
Gomez-Munoz, A., Kong, J. Y., Parhar, K., Wang, S. W., Gangoiti, P., Gonzalez, M., Eivemark, S., Salh, B., Duronio, V. and Steinbrecher, U. P. (2005). Ceramide-1-phosphate promotes cell survival through activation of the phosphatidylinositol 3-kinase/protein kinase B pathway. FEBS Lett. 579, 3744-3750.[CrossRef][Medline]
Goparaju, S. K., Jolly, P. S., Watterson, K. R., Bektas, M., Alvarez, S., Sarkar, S., Mel, L., Ishii, I., Chun, J., Milstien, S. et al. (2005). The S1P2 receptor negatively regulates platelet-derived growth factor-induced motility and proliferation. Mol. Cell. Biol. 25, 4237-4249.
Graeler, M. and Goetzl, E. J. (2002). Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 16, 1874-1878.
Hancock, C. N., Dangi, S. and Shapiro, P. (2005). Protein phosphatase 2A activity associated with Golgi membranes during the G2/M phase may regulate phosphorylation of ERK2. J. Biol. Chem. 280, 11590-11598.
Hannun, Y. A. and Obeid, L. M. (2002). The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J. Biol. Chem. 277, 25487-25850.
Herr, D. R., Fyrst, H., Phan, V., Heinecke, K., Georges, R., Harris, G. L. and Saba, J. D. (2003). Sply regulation of sphingolipid signaling molecules is essential for Drosophila development. Development 130, 2443-2453.
Herr, D. R., Fyrst, H., Creason, M. B., Phan, V. H., Saba, J. D. and Harris, G. L. (2004). Characterization of the Drosophila sphingosine kinases and requirement for Sk2 in normal reproductive function. J. Biol. Chem. 279, 12685-12694.
Hixon, M. S., Ball, A. and Gelb, M. H. (1998). Calcium-dependent and -independent interfacial binding and catalysis of cytosolic group IV phospholipase A2. Biochemistry 37, 8516-8526.[CrossRef][Medline]
Hobson, J. P., Rosenfeldt, H. M., Barak, L. S., Olivera, A., Poulton, S., Caron, M. G., Milstien, S. and Spiegel, S. (2001). Role of the sphingosine-1-phosphate receptor EDG-1 in PDGF-induced cell motility. Science 291, 1800-1803.
Jolly, P. S., Bektas, M., Olivera, A., Gonzalez-Espinosa, C., Proia, R. L., Rivera, J., Milstien, S. and Spiegel, S. (2004). Transactivation of sphingosine-1-phosphate receptors by Fc{epsilon}RI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959-970.
Jolly, P. S., Bektas, M., Watterson, K. R., Sankala, H., Payne, S. G., Milstien, S. and Spiegel, S. (2005). Expression of SphK1 impairs degranulation and motility of RBL-2H3 mast cells by desensitizing S1P receptors. Blood 105, 4736-4742.
Kolesnick, R. N. and Hemer, M. R. (1990). Characterization of a ceramide kinase activity from human leukemia (HL-60) cells. Separation from diacylglycerol kinase activity. J. Biol. Chem. 265, 18803-18808.
Lawrence, T., Bebien, M., Liu, G. Y., Nizet, V. and Karin, M. (2005). IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434, 1138-1143.[CrossRef][Medline]
Liang, H., Yao, N., Song, J. T., Luo, S., Lu, H. and Greenberg, J. T. (2003). Ceramides modulate programmed cell death in plants. Genes Dev. 17, 2636-2641.
Limaye, V. S., Li, X., Hahn, C., Xia, P., Berndt, M. C., Vadas, M. A. and Gamble, J. R. (2005). Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members. Blood 105, 3169-3177.
Lo, C. G., Xu, Y., Proia, R. L. and Cyster, J. G. (2005). Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 201, 291-301.
Mandala, S., Hajdu, R., Bergstrom, J., Quackenbush, E., Xie, J., Milligan, J., Thornton, R., Shei, G. J., Card, D., Keohane, C. et al. (2002). Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346-349.
Massiello, A., Salas, A. M., Pinkerman, R. L., Roddy, P., Roesser, J. R. and Chalfant, C. E. (2004). Identification of two RNA cis-elements that function to regulate the 5' splice site selection of Bcl-x pre-mRNA in response to ceramide. J. Biol. Chem. 279, 15799-15804.
Matloubian, M., Lo, C. G., Cinamon, G., Lesneski, M. J., Xu, Y., Brinkmann, V., Allende, M. L., Proia, R. L. and Cyster, J. G. (2004). Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355-360.[CrossRef][Medline]
Meyer zu Heringdorf, D., Liliom, K., Schaefer, M., Danneberg, K., Jaggar, J. H., Tigyi, G. and Jakobs, K. H. (2003). Photolysis of intracellular caged sphingosine-1-phosphate causes Ca2+ mobilization independently of G-protein-coupled receptors. FEBS Lett. 554, 443-449.[CrossRef][Medline]
Min, J., Traynor, D., Stegner, A. L., Zhang, L., Hanigan, M. H., Alexander, H. and Alexander, S. (2005). Sphingosine kinase regulates the sensitivity of dictyostelium discoideum cells to the anticancer drug cisplatin. Eukaryot. Cell 4, 178-189.
Mitsutake, S., Kim, T. J., Inagaki, Y., Kato, M., Yamashita, T. and Igarashi, Y. (2004). Ceramide kinase is a mediator of calcium-dependent degranulation in mast cells. J. Biol. Chem. 279, 17570-17577.
Nakanishi, C. and Toi, M. (2005). Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nature Rev. Cancer 5, 297-309.[CrossRef][Medline]
Ng, C. K., Carr, K., McAinsh, M. R., Powell, B. and Hetherington, A. M. (2001). Drought-induced guard cell signal transduction involves sphingosine-1-phosphate. Nature 410, 596-599.[CrossRef][Medline]
Ogretmen, B. and Hannun, Y. A. (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Rev. Cancer 4, 604-616.[CrossRef][Medline]
Olivera, A. and Rivera, J. (2005). Sphingolipids and the balancing of immune cell function: lessons from the mast cell. J. Immunol. 174, 1153-1158.
Olivera, A., Rosenfeldt, H. M., Bektas, M., Wang, F., Ishii, I., Chun, J., Milstien, S. and Spiegel, S. (2003). Sphingosine kinase type 1 Induces G12/13-mediated stress fiber formation yet promotes growth and survival independent of G protein coupled receptors. J. Biol. Chem. 278, 46452-46460.
Pandey, S. and Assmann, S. M. (2004). The Arabidopsis putative G protein-coupled receptor GCR1 interacts with the G protein alpha subunit GPA1 and regulates abscisic acid signaling. Plant Cell 16, 1616-1632.
Pettus, B. J., Chalfant, C. E. and Hannun, Y. A. (2002). Ceramide in apoptosis: an overview and current perspectives. Biochim. Biophys. Acta 1585, 114-125.[Medline]
Pettus, B. J., Bielawska, A., Spiegel, S., Roddy, P., Hannun, Y. A. and Chalfant, C. E. (2003a). Ceramide kinase mediates cytokine-and calcium ionophore-induced arachidonic acid release. J. Biol. Chem. 278, 38206-38213.
Pettus, B. J., Bielawski, J., Porcelli, A. M., Reames, D. L., Johnson, K. R., Morrow, J., Chalfant, C. E., Obeid, L. M. and Hannun, Y. A. (2003b). The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. FASEB J. 17, 1411-1421.
Pettus, B. J., Bielawska, A., Subramanian, P., Wijesinghe, D. S., Maceyka, M., Leslie, C. C., Evans, J. H., Freiberg, J., Roddy, P., Hannun, Y. A. et al. (2004). Ceramide-1-phosphate is a direct activator of cytosolic phospholipase A2. J. Biol. Chem. 279, 11320-11326.
Pettus, B. J., Kitatani, K., Chalfant, C. E., Taha, T. A., Kawamori, T., Bielawski, J., Obeid, L. and Hannun, Y. A. (2005). The coordination of prostaglandin E2 production by sphingosine-1-phosphate and ceramide-1-phosphate. Mol. Pharmacol. 68, 330-335.
Rosen, H. and Goetzl, E. J. (2005). Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nature Rev. Immunol. 5, 560-570.[CrossRef][Medline]
Rosenfeldt, H. M., Hobson, J. P., Maceyka, M., Olivera, A., Nava, V. E., Milstien, S. and Spiegel, S. (2001). EDG-1 links the PDGF receptor to Src and focal adhesion kinase activation leading to lamellipodia formation and cell migration. FASEB J. 15, 2649-2659.
Scott, K. F., Bryant, K. J. and Bidgood, M. J. (1999). Functional coupling and differential regulation of the phospholipase A2-cyclooxygenase pathways in inflammation. J. Leukoc. Biol. 66, 535-541.[Abstract]
Shu, X., Wu, W., Mosteller, R. D. and Broek, D. (2002). Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Mol. Cell. Biol. 22, 7758-7768.
Spiegel, S. and Milstien, S. (2003). Sphingosine-1-phosphate: an enigmatic signalling lipid. Nature Rev. Mol. Cell. Biol. 4, 397-407.[CrossRef][Medline]
Subramanian, P., Stahelin, R. V., Szulc, Z., Bielawska, A., Cho, W. and Chalfant, C. E. (2005). Ceramide 1-phosphate acts as a positive allosteric activator of group IVA cytosolic phospholipase A2alpha and enhances the interaction of the enzyme with phosphatidylcholine. J. Biol. Chem. 280, 17601-17607.
Sugiura, M., Kono, K., Liu, H., Shimizugawa, T., Minekura, H., Spiegel, S. and Kohama, T. (2002). Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization. J. Biol. Chem. 277, 23294-23300.
Suomalainen, L., Pentikainen, V. and Dunkel, L. (2005). Sphingosine-1-phosphate inhibits nuclear factor kappaB activation and germ cell apoptosis in the human testis independently of its receptors. Am. J. Pathol. 166, 773-781.
Tornquist, K., Blom, T., Shariatmadari, R. and Pasternack, M. (2004). Ceramide 1-phosphate enhances calcium entry through voltage-operated calcium channels by a protein kinase C-dependent mechanism in GH4C1 rat pituitary cells. Biochem. J. 380, 661-668.[CrossRef][Medline]
Ullah, H., Chen, J. G., Young, J. C., Im, K. H., Sussman, M. R. and Jones, A. M. (2001). Modulation of cell proliferation by heterotrimeric G protein in Arabidopsis. Science 292, 2066-2069.
Vaidyanathan, G., Cismowski, M. J., Wang, G., Vincent, T. S., Brown, K. D. and Lanier, S. M. (2004). The Ras-related protein AGS1/RASD1 suppresses cell growth. Oncogene 23, 5858-5863.[CrossRef][Medline]
Wu, W., Shu, X., Hovsepyan, H., Mosteller, R. D. and Broek, D. (2003). VEGF receptor expression and signaling in human bladder tumors. Oncogene 22, 3361-3370.[CrossRef][Medline]
Xia, P., Wang, L., Moretti, P. A., Albanese, N., Chai, F., Pitson, S. M., D'Andrea, R. J., Gamble, J. R. and Vadas, M. A. (2002). Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling. J. Biol. Chem. 277, 7996-8003.