Apoptosis and survival - Ceramides signaling pathway

Ceramides signaling pathway

Ceramides regulate diverse signaling pathways involving apoptosis, cell senescence, the cell cycle, and differentiation. Preliminary Ceramides effects are antagonistic to growth and survival [1], [2].

Ceramides levels are elevated in response to diverse stress challenges including irradiation, heat and cytokines. For instance, Ceramides act as second messengers in tumor necrosis factor (TNF-alpha)/ Tumor necrosis factor receptor superfamily, member 1 (TNF-R1) signaling [1], [2], [3]. TNF-R1 binds adaptor Neutral sphingomyelinase activation associated factor (FAN) that transducer signal to Neutral sphingomyelinase [4]. TNF-R1 activates Acid sphingomyelinase via pathway, which require TNFRSF1A-associated via death domain (TRADD)/ Fas (TNFRSF6)-associated via death domain (FADD) adaptor proteins [5], [6]. Acid and Neutral sphingomyelinases probably can trigger different TNF-alpha-induced pathways. Ceramide produced by Neutral sphingomyelinase stimulates Ceramides-activated Mitogen-activated protein kinase 1 and 3 (ERK1/2) cascade and Acid sphingomyelinase may couple the TNF-R1 to the secretary pathway and to apoptosis via Cathepsin D [6].

Ceramides induce TNF-alpha/ ERK1/2 cascade via Kinase suppressor of ras 1 (KSR). KSR is a molecular scaffold coordinating the Raf (v-myc myelocytomatosis viral oncogene homolog (c-Raf-1))/ Mitogen-activated protein kinase kinase 1 (MEK1) interaction [7], [8], [9]. Ceramides signaling in some cases was shown to be dependent on v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) [8], [10]. This can be explained by scaffolding properties of KSR [9]. TNF-alpha and Ceramides activation of H-Ras leads to Phosphoinositide-3-kinase (PI3K reg class IA (p85))/ PI3K cat) activation and then to fibroblasts proliferation [10]. And controversially, KSR/ c-Raf-1/ MEK1(MAP2K1) [8]/ ERK1/2 [7] -dependent pathway can lead to inhibition of PI3K/ v-akt murine thymoma viral oncogene homolog (AKT(PKB)) activation. This prevents BCL2-associated agonist of cell death (BAD) phosphorylation and leads to apoptosis in COS-7 cells. The mechanism is not elucidated [7], [8], [11]. Also, Inhibition of AKT(PKB) by Ceramides can be a pathway of Ceramides-induced inhibition of Insulin-induced glucose uptake. Ceramides can suppress AKT(PKB) activity without PI3K inhibition. This inhibition depends on protein phosphatase 2 (PP2A)-mediated dephosphorylation and by blocking AKT(PKB) translocation to plasma membrane via Protein kinase C zeta (PKC-zeta). Ceramides can directly bind and activate PKC-zeta and PP2A. [12], [13], [14], [15].

Ceramides can participate in Fas ligand (FasL(TNFSF6)) signaling leading to apoptosis [16], [17], [18]. FasL(TNFSF6) binds Fas (FasR(CD95)) that induces Caspase-8-mediated Acid sphingomyelinase [19] and Caspase-3-mediated Neutral sphingomyelinase activation [20] and production of Ceramides. Ceramides then promotes Ras-dependent apoptosis [21].

PKC-zeta directly binds and activates Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1)), Mitogen-activated protein kinase kinase 4 (MEK4(MAP2K4)), Mitogen-activated protein kinase 8 (JNK1(MAPK8)) [22]. Activation of JNK1(MAPK8) pathway by TNF-alpha and Ceramides leads to apoptosis [23]. Ceramides-induced mitogen-activated protein kinase kinase kinase 7 (TAK1(MAP3K7)) also participates in this process [11], [24].

Ceramides via Cathepsin D/ BH3 interacting domain death agonist (Bid)/ Cytochrome c mediates TNF-alpha induced apoptosis. Mitochondrial pathway of apoptosis includes activation of Caspases-3 and Caspases-9 [25], [26], [27].

References

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