Ceramide Pathway
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Ceramide Pathway
The SM (Sphingomyelin) pathway is an evolutionarily conserved stress response system linking diverse environmental stresses (Ultraviolet, Heat Shock, Oxidative Stress, and Ionizing Radiation) to cellular effector pathways. Ceramide is the second messenger in this system and can be generated either by hydrolysis of SM through SM-specific PLC (Phospholipase-C) termed SMases (Sphingomyelinases) or by de novo synthesis through the enzyme Ceramide Synthase (Ref.1). There are two classes of SMase, acidic (A-Smase) and neutral (N-Smase). Stress stimuli such as, TNF-Alpha (Tumor Necrosis Factor-Alpha), lipopolysaccharide, and some chemotherapy drugs such as doxorubicin also mediate apoptosis by generation of the lipid second messenger, Ceramide. A specific interaction between the FAN (Factor Associated with N-Smase activation) protein and TNF-Alpha associated proteins (TRADD, TRAFs and RIP) regulates Ceramide production by N-Smase, a step crucial in TNF signaling.

Sphingolipids are integral components of eukaryotic cell membranes and their metabolisms generates and interconvert various metabolites including Ceramide, Sphingosine, and S-1P (Sphingosine-1 Phosphate), which affect cell cycle, apoptosis, and angiogenesis (Ref.2). S-1P activates the heterotrimeric orphan receptor EDG /S1PRs (Endothelial Differentiation, Sphingolipid GPCR) to stimulate SphK1 (S-1P Kinase) and to generate intracellular S-1P from Sph (Sphingosine). S-1P functions in an autocrine or paracrine fashion to stimulate the EDG /S1PRs (Endothelial Differentiation, Sphingolipid GPCR) that are present on the cell surface of the same or nearby cells. Coupling of EDG /S1PRs to diverse G-Proteins leads to activation of numerous downstream signalling pathways. TNF-Alpha and other cytokines stimulate SphK1 leading to the activation of the transcription factors NF-KappaB and AP-1 (Adaptor Protein-1), which is essential for the prevention of apoptosis. Either alone, or in combination with other signals, Ceramide, once generated, propagates the cellular stress response by coupling to effector systems. Different cells react differently to elevations in Ceramide: some cells launch the apoptotic program; others commit to terminal differentiation, or undergo cell cycle arrest, depending on the effector pathways activated (Ref.1). Well-defined targets are CAPK (Ceramide-Activated Protein Kinase), Ras , CAPP (Ceramide-Activated Protein Phosphatase), PP2A, and PKC-Delta (Protein Kinase-C-Delta). Ceramide binding to Raf1 leads to sequestration of Raf1 into inactive Ras-Raf1 complexes. In addition, the putative GEF (Guanine Nucleotide Exchange Factor), Vav, a potential activator of Ras and related proteins in hematopoietic cells, serve as a direct effector of Ceramide.

Ceramide directly regulates KSR (Kinase Suppressor of Ras), PLA2 (Phospholipase-A2), Cathepsin-D, various PKC (Protein Kinase-C) isoforms, and c-Raf1 (Ref.8). Ceramide induce apoptosis by activating pro-death pathways through activation of JNK (c-Jun N-terminal kinase) /SAPK (Stress-Activated Protein Kinase), and by promoting dephosphorylation of the pro-survival protein BCL2, BAX and the pro-apoptotic protein BAD. The dephosphorylation of BCL2 is mediated by CAPP activity, whereas dephosphorylation of BAD by Ceramide is through activation of the KSR and subsequent activation of MEK1 (MAPK/ERK Kinase) pathway and MAPK (Mitogen-Activated Protein Kinase), leading to decreased PKB (Protein Kinase-B) activation (Ref.3). Ceramide also directly inhibits PI3K (Phosphoinositide-3 Kinase), together blocking Akt/PKB activity and BAD phosphorylation. Phosphorylated CAPK also activates Raf1, which then phosphorylates and activates the two dual specificity protein kinases, MAPK, ERK1/2(Extracellular Signal-Regulated Kinase), triggering the MAPK/ERK pathway. Consistent with this, stimulation of the SM pathway induces ERK activation and NF-KappaB (Nuclear Factor kappa-B) translocation. Activation of JNK by Ceramides regulates the transcription factor AP-1 (Activating Protein-1) and induces the expression of a novel monocyte/macrophage differentiation-dependent gene (Ref.4). Ceramide activates the SAPK cascade via direct activation of PKC-Delta (Protein Kinase-C). Upon activation by Ceramide, PKC-Delta forms a signaling complex with upstream components of the SAPK cascade, including MEKK1 (MAPK/ERK Kinase Kinase) and SEK1 (or MAP2K4). Ceramide also activates proteinases including the Caspases , especially Caspase3, (otherwise known as the ICE family (IL-3 Beta Converting Enzyme) of proteases such as CPP32) that mediate intracellular protein degradation (Ref.5). Ceramide also activates endonucleases that are responsible for DNA cleavage. A-Smase-released Ceramide binds directly to PLA2 and Cathepsin-D, which induce apoptosis (Ref.8).

To date, several agents have been described to stimulate the SM-Ceramide pathway, including cytokines such as TNF-Alpha, IL-1Beta (Interleukin-1Beta), Interferon-Gamma, NGF (Nerve Growth Factor), anti-CD28, anti-Fas antibodies, anticancer drugs, ionizing radiations, ultraviolet radiation, chemotherapeutic and genotoxic chemicals, which initiate numerous physiological processes (Ref.6). Depending upon the cell type (monoblastic leukemia cells, endothelial cells, fibroblasts, pheochromocytoma cells, and oligodendrocytes), Ceramides act as modulator of immune cell differentiation, mitochondrial respiration releasing CytoC (Cytochrome-C), inflammation, cell cycle progression, apoptosis, and the stress response. Ceramide is now emerging as an important component of mitochondrial-dependent apoptosis and in the regulation of stress responses. In addition to its role in apoptosis, Ceramide induces G0/G1 cell cycle arrest, due to the induction of dephosphorylation of the Rb (Retinoblastoma) gene product (Ref.5). Ceramide also acts as an endogenous modulator of leukocyte function because it inhibits the respiratory burst and phagocytosis (Ref.6). Ceramide blocks Insulin signaling by preventing the activation of Akt/PKB pathway. Thus, the ability of Ceramide to induce growth arrest, without inducing significant apoptosis or necrosis, may be of therapeutic value in the prevention or control of cell proliferation during inflammatory renal and vascular diseases. Over the past few years there has been an escalating interest in exploring the role of Ceramide and its metabolites in tissue physiology and pathophysiology. Typically, strategies that elevate cellular Ceramide are being used for therapies aimed to arrest growth or promote apoptosis (Ref.7).