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Sphingolipid Signaling 91 Sphingolipid Signaling 91 10 Sphingolipid Signaling Implications for Vascular Biology Margaret M. Harnett SUMMARY Sphingolipids comprise a family (>300) of lipids that are characterized by their sphingoid backbone but differ in their headgroup constituents. Complex headgroups involving G-glucose or galactose linkages (cerebrosides), sialic acid (gangliosides), or sulphated-galactosyl linkages (sulphatides) are known as glycosphingolipids and have long been recognized as playing roles in maintaining the structural integrity of membranes and mediating cell-cell recognition and interactions. In contrast, the addition of phosphorylcholine to ceramide by sphingomyelin synthase generates the prototypic phosphosphingolipid, sphingomyelin. These phosphosphingolipids are present in much lower concentrations, and recent interest has focused on the role of three sphingomyelin-derived second messengers—ceramide, sphingosine, and sphingosine-1-phosphate (S1P)—in regulating cell fate (death/survival) decisions. Moreover, there is in- creasing evidence that sphingolipids can also signal by modulating receptor function by regulating the formation of lipid rafts, specialized membrane signaling domains that are enriched in cholesterol and sphingolipids. This review will discuss the signaling roles of the sphingolipid-derived second messengers and the implications for vascular biology. Key Words: Sphingolipids; signal transduction; ceramide; sphingosine-1-phosphate; Edg receptors; calcium. 1. INTRODUCTION Until the late 1970s, lipids were considered to play simply a structural role in the generation and maintenance of cell-membrane permeability barriers due to their amphipathic nature and ability to form bilayers. However, at this time it was discovered that the “second messenger” molecule re- quired for the receptor-mediated mobilization of intracellular stores of calcium was inositol 1,4,5- trisphosphate (IP3), a product of the phospholipase C-mediated hydrolysis of a minor phospholipid species phosphatidylinositol 4,5-bisphosphate (PIP2) (1). Moreover, the alternative product of PIP2 hydrolysis, diacylglycerol (DAG), was found to be the physiological activator of a family of key downstream signaling serine/threonine protein kinases known generically as protein kinase C (PKC), which had previously been identified as the target of the tumor promoter phorbol myristate acetate (PMA). The importance of these lipid-derived second messengers was underlined by the finding that receptor-mediated responses such as exocytosis or proliferation of many cell types could be mim- icked by pharmacological activation of PKC by PMA and calcium mobilization by calcium iono- phores (2). Moreover, PIP2 was also found to be the substrate for the lipid kinase phosphoinositide From: Cell Signaling in Vascular Inflammation Edited by: J. Bhattacharya © Humana Press Inc., Totowa, NJ 91 92 Harnett Fig. 1. Receptor-coupled lipid signal transduction. G protein-coupled receptors or growth-factor receptor tyrosine kinases couple to one or more phospholipid and sphingolipid signaling pathways to transduce signals leading to apoptosis, survival, differentiation, or proliferation. These signals may crosstalk: for example, in many cell types tumor necrosis factor receptor (TNF-R) coupling to SMase-mediated generation of ceramide is dependent on prior induction of AA via cPLA2. Likewise, in monocytes, FcLRI coupling to sphingosine kinase and S1P generation is dependent on upstream coupling to PI 3K and PtdCho-PLD. Abbreviations: AA, arachi- donic acid; Akt, the proto-oncogene ser/thr kinase, Akt; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PA, phosphatiditic acid; PI 3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PtdCho, phosphatidylcholine; S1P, sphingosine-1-phosphate; SM, sphingomyelin; SMase, sphingomyelinase. 3-kinase (PI 3K), which generates the lipid second messenger PI (3,4,5)P3, a key player in many cellular responses, including the movement of organelle membranes, shape alteration through rear- rangement of cytoskeletal actin, rescue from apoptosis, transformation, and chemotaxis (3). These findings triggered an explosive burst of research into the role of lipids and their products as key players in receptor-mediated signal transduction (1–4). The fact that PIP2 was a minor phospholipid species found in the inner leaflet of the plasma mem- brane fitted with the then current dogma that second-messenger signals had to be transient signals. However, it became apparent that for many prolonged responses such as proliferation, sustained and substantial generation of DAG and/or PKC activation was required, suggesting that such DAG was generated from alternative sources (Fig. 1). This proposal led to the finding that hydrolysis of the major phospholipid phosphatidylcholine (PtdCho; <40% plasma membrane lipid) provided a range of lipid second messengers. Indeed, PtdCho can be hydrolyzed by (1) PLC, to generate phosphocholine (PC) and DAG; (2) phospholipase D (PLD), to generate choline and phosphatiditic acid (PA); and (3) phospholipase A2, to produce arachidonic acid (AA) and lysophosphatidylcholine (5,6). It is now widely established that DAG, PA (these are interconvertible), and AA all can have second-messenger function (7,8), and there is increasing evidence that PC can also function in this manner (9). Sphingolipid Signaling 93 Fig. 2. Sphingolipid metabolic pathways. Serine palmitoyltransferase condenses palmitoyl-CoA plus serine to generate 3-oxosphinganine, which is then converted to sphinganine by oxosphinganine reductase. Sphinganine is then converted to dihydroceramide by dihydroceramide synthase, the target of the inhibitor fumonisin B. Dihydroceramide is then converted to ceramide by dihydroceramide desaturase (de novo ceramide generation). Ceramide can then be incorporated into phosphosphingolipids such as sphingomyelin by sphingomelin synthase or alternatively, into glycosphingolipids by enzymes such as glucosylceramide syn- thase. During prosurvival signaling ceramide may be metabolized to sphingosine by ceramidase and subse- quently to sphingosine-1-phosphate by sphingosine kinase. Sphingosine-1-phosphate can then be degraded by sphingosine-1-phosphate lyase or reconverted to sphingosine by sphingosine-1-phosphatase. Ceramide can also be generated by sphingomyelinase-mediated hydrolysis of sphingomyelin. The finding that PtdCho is generally found in the outer leaflet of the plasma membrane also dem- onstrated that bioactive lipids need not be located in the inner leaflet of the plasma membrane, and suggested that all membrane lipids could potentially act as sources of lipid second messengers. In- deed, a wealth of data in the last 10–15 yr has implicated key signaling roles for another major class of lipids, the sphingolipids. Sphingolipids, which are found in all eukaryotes and can be broadly subdivided into glycophingolipids and phosphosphingolipids, comprise a family (>300) of lipids that are characterized by their sphingoid backbone but differ in their headgroup constituents (Fig. 2). Complex headgroups involving G-glucose or galactose linkages (cerebrosides), sialic acid (ganglio- sides), or sulphated-galactosyl linkages (sulphatides) are known as glycosphingolipids and have long been recognized as playing roles in maintaining the structural integrity of membranes and mediating cell–cell recognition and interactions. In contrast, the addition of phosphorylcholine to ceramide by sphingomyelin synthase generates the prototypic phosphosphingolipid sphingomyelin. These phosphosphingolipids are present in much lower concentrations, and recent interest has focused on 94 Harnett the role of three sphingomyelin-derived second messengers—ceramide, sphingosine, and sphin- gosine-1-phosphate (S1P)—in regulating cell fate (death/survival) decisions (10–16). Moreover, there is increasing evidence that sphingolipids can also signal by modulating receptor function by regulat- ing the formation of lipid rafts, specialized membrane signaling domains that are enriched in choles- terol and sphingolipids (17–20). This review will discuss the signaling roles of the sphingolipid-derived second messengers and the implications for vascular biology. 2. CERAMIDE AND APOPTOSIS Ceramide, which can be generated either by hydrolysis of the sphingolipid sphingomyelin (SM) by a family of acid and neutral sphingomyelinases (SMase) or by de novo synthesis, has been pro- posed to be a coordinator of stress responses (10,12,18,21,22). Indeed, stress signals such as cytokines (e.g., tumor necrosis factor [TNF]), heat, ultraviolet (UV) irradiation, hypoxia, and chemotherapeu- tic agents (e.g., doxorubicin, etoposide) all induce SMase and/or de novo generation of ceramide, and this induction of ceramide correlates with apoptosis. Indeed, it is well established that such apoptosis can be mimicked by pharmacological application of the short ceramides C2-ceramide or C6-ceramide. Ceramide-mediated apoptosis appears to act by disrupting mitochondrial integrity, leading to the activation of caspases and consequent cellular disassembly. Thus, the role of SMase activation and ceramide generation in the outer leaflet of the plasma membrane in transducing apoptosis is not clear, and indeed the generation of acid SMase knockout mice have further questioned the likelihood of an essential role of this pool of ceramide in transducing
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