Ceramide Signaling

Ceramide is the second messenger that can be generated either by hydrolysis of SM through SM-specific PLC termed SMases or by de novo synthesis through the enzyme Ceramide Synthase. There are two classes of SMase,acidic (A-Smase) and neutral (N-Smase). Stress stimuli such as, TNF-α, 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, protein and TNF-α 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, which affect cell cycle, apoptosis, and angiogenesis. S1P activates the heterotrimeric orphan receptor EDG/S1PRs to stimulate SphK1 and to generate intracellular S-1P from Sph (Sphingosine). S-1P functions in an autocrine or paracrine fashion to stimulate the EDG/S1PRs 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-α and other cytokines stimulate SphK1 leading to the activation of the transcription factors NF-κB and AP-1, which is essential for the prevention of apoptosis.Ceramide binding to Raf1 leads to sequestration of Raf1 into inactive Ras-Raf1 complexes. In addition, the putative GEF, Vav,a potential activator of Ras and related proteins in hematopoietic cells, serve as a direct effector of Ceramide.Ceramide directly regulates KSR, PLA2, Cathepsin-D, various PKC isoforms, and c-Raf1. Ceramide induce apoptosis by activating pro-death pathways through activation of JNK/SAPK, 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 pathway and MAPK, leading to decreased PKB activation. Ceramide also directly inhibits PI3K, 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, triggering the MAPK/ERK pathway. Consistent with this, stimulation of the SM pathway induces ERK activation and NF-κB translocation. Activation of JNK by Ceramides regulates the transcription factor AP-1 and induces the expression of a novel monocyte/macrophage differentiation-dependent gene. Ceramide activates the SAPK cascade via direct activation of PKC-δ. Upon activation by Ceramide, PKC-δ forms a signaling complex with upstream components of the SAPK cascade, including MEKK1 and SEK1. Ceramide also activates proteinases including the Caspases, especially Caspase-3, that mediate intracellular protein degradation. Ceramide also activates endonucleases that are responsible for DNA cleavage. A-Smase-released Ceramide binds directly to PLA2 and Cathepsin-D, which induce apoptosis.Ceramide induces G0/G1 cell cycle arrest,due to the induction of dephosphorylation of the Retinoblastoma gene product. Ceramide also acts as an endogenous modulator of leukocyte function because it inhibits the respiratory burst and phagocytosis. 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. The role of Ceramide and its metabolites in tissue physiology and pathophysiology.