Signalling pathways induced by sphingolipids

From LipidomicsWiki

Several growth factors, cytokines and oxidized lipoproteins, which play a role in atherogenic processes, stimulate signalling pathways leading to sphingomyelin hydrolysis and generation of ceramide and other metabolites. Therefore, sphingomyelinases can be regarded upstream elements of signalling pathways.

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The biological response to newly formed ceramide and its metabolites varies depending on the cell type and the spectrum of responses includes cell cycle arrest (Nickels and Broach, 1996), initiation of cell proliferation and differentiation (Testi 1996), induction of apoptosis (Hannun and Obeid, 1995, Zhang et al, 1996). Ceramide induces its signals through either direct interactions with proteins or via activation of different signalling pathways (Dobrowsky et al, 1994, Liu et al. 1999). Ceramide has been reported to regulate directly or indirectly the activity of a number of enzymes and signalling components (Perry and Hannun, 1998). One primary target of ceramide is ceramide-activated protein kinase (CAPK), a membrane-associated prolinedirected serine/threonine kinase. Activated CAPK phosphorylates Raf-1 kinase, which in turn can trigger the extracellular signal-regulated (ERK) cascade and arachidonic acid production by PLA2. A second potential primary mediator of the ceramide signalling pathway is ceramide-activated protein phosphatase (CAPP), which is a member of the 2A family of protein phosphatases (PP2A). Ceramide was also shown to bind and regulate the activity of protein kinase C epsilon (PKCξ), the atypical isoform of PKC, which is not activated by DAG or phorbol esters (Wang et al. 1999). It was demonstrated that ceramide binding to PKCξ leads to phosphorylation and activation of the kinase, and its translocation to the nucleus. Only recently, the role of ceramide in apoAI-mediated cholesterol efflux has been documented (Witting et al. 2003). In cells expressing ABCA1, ceramide caused a significant increase in cholesterol efflux to apoAI accompanied by upregulation of ABCA1. Ceramide has been regarded as a lipid second messenger but one of the recent manuscripts by Blitterswijk (van Blitterswijk et al. 2003) questions this statement. In contrast to already recognized second messengers, ceramide seems to have a too long formation time upon induction, its physiological targets are not well defined and there is a lack of the precisely defined consensus motif in the primary sequence of its target proteins. The role of sphingosine-1-phosphate as a classical second messenger is currently under debate. S1P is present at a steady-state level in the cytosol, however, upon cell perturbation, its level transiently rises (Spiegel and Milstien, 2002), which is characteristic for second messengers. The intracellular targets of sphingosine-1-phosphate have not been yet identified and it has been shown that S1P binding to its receptors stimulates sphingosine kinase to increase its own intracellular level (Meyer zu Heringdorf et al. 2001).

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The cell surface receptors for sphingosine-1-phosphate have been recently identified (Tab. 10). Up till now 5 receptors were identified and named according to the Nomenclature Committee of the Internaltional Union of Pharmacology as S1P1 to S1P5 receptors (Chun et al. 2002). All five receptors have been shown to bind sphingosine-1-phosphate with high affinity and activate several intracellular processes related to angiogenesis, apoptosis, atherosclerosis, migration and proliferation (Fig.36) (Lee et al. 1999, Kimura et al. 2000, Tamama et al. 2001). The receptors for sphingosine-1-phosphate belong to the edg (endothelial differentiation gene) family of the seven transmembrane G protein-coupled receptor superfamily. The edg-1 receptor originally cloned, as an orphan receptor gene that is upregulated in HUVEC cells upon stimulation with phorbol esters is a prototypic member of this family.

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Sphingosine-1-phosphate has been shown recently to act not only intracellularly but also extracellularly. The cystic fibrosis transmembrane regulator (CFTR) has been ascribed a role of a specific transporter of sphingosine-1-phosphate into the cell. CFTR would then function as a terminator of extracellular signals and initiator of intracellular signals (Boujaoude et al. 2001). Recently, several G protein-coupled receptors encoded by the family of edg have been shown to bind LPA and S-1-P and transduce responses of cAMP, Ca2+, MAP kinases and gene transcription (Okamoto, et al. 1998, Moolenaar, 1999). Up till now, it has been stated that edg-1 and edg-3 bind Sph-1-P with high affinity and specificity (Tab. 9). The Edg receptor family belongs to the seven-transmembrane G protein-coupled receptor superfamily and consists of a still growing number of members. To date, the family consists of at least eight independent subtypes subdivided into those specific mainly for LPA and those that bind Sph-1-P with high affinity (Moolenaar, 1999). The edg family of receptors are differentially expressed, mainly in the cardiovascular and nervous system, and are coupled to a variety of G-proteins. The results from many studies indicate that LPA receptors couple to three distinct G proteins : Gq, which links the receptor to phospholipase C, Gi, which triggers Ras-GTP accumulation and inhibition of adenylyl cyclase; and G12/13, which mediates Rho activation (Moolenaar et al. 1997). Despite this similarity and the finding that Sph-1-P can occur extracellularly, crossdesensitization experiments showed that Sph-1-P is not an agonist for LPA receptors. Recent data also demonstrated that the capacity of LPA to suppress apoptosis in some types of cells is significantly lower in comparison with that of Sph-1-P (Goetzl et al. 1999).


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