Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway

Bénéteau, Marie; Pizon, Mathieu; Chaigne-Delalande, Benjamin; Daburon, Sophie; Maillard, Patrick; Giorgi, Francesca De; Ichas, François; Rebillard, Amélie; Dimanche‐Boitrel, Marie‐Thérèse; Taupin, Jean‐Luc; Moreau, Jean-François; Legembre, Patrick

doi:10.1158/1541-7786.mcr-07-0331

Cited by 47 publications

(67 citation statements)

References 49 publications

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“…In contrast to CD95L, the CD95 capping and its redistribution into the lipid rafts occurred in cells treated with antitumoral agents such as aplidin, 30 edelfosine 31,32 or semaphorin3A 33 and relied on the actin cytoskeleton remodeling. The partition of CD95 into the lipid rafts and the subsequent induction of the apoptotic signal observed in cells treated with various antitumoral agents such as cisplatin, 34 edelfosine 31,32 or resveratrol 35 occurred independent of ligand expression.…”

Section: Discussionmentioning

confidence: 88%

CD95 engagement mediates actin-independent and -dependent apoptotic signals

et al. 2009

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CD95 is a death receptor whose stimulation by either the physiologic ligand CD95L or the agonistic antibodies leads to the formation of a multi-molecular complex termed DISC (death-inducing signaling complex) and the subsequent induction of a caspase-driven apoptotic signal. According to the magnitude of the DISC formation, two types of cells have been identified. Although type I cells generate an important DISC, the complex is barely found in type II cells. Analyzing the early stages preceding the DISC formation, we found that unlike CD95L, the commonly used agonistic antibody APO1-3 internalized the death receptor. Using inhibitors of actin polymerization, we showed that the remodeling of the actin cytoskeleton did not alter the capping of the CD95 receptor or its partitioning into the lipid rafts. In addition, whereas the disruption of F-actin prevented the internalization of CD95, the DISC formation and the apoptotic signal induced by the agonistic antibody APO1-3 in type I cells, it did not affect the signal triggered by the soluble and membrane-bound CD95L, regardless of the type of cells. In conclusion, the addition of APO1-3 on type I cells triggers an actin-dependent apoptotic signal, which is absent or marginal in cells (both types I and II) treated with CD95L.

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Section: Discussionmentioning

confidence: 88%

CD95 engagement mediates actin-independent and -dependent apoptotic signals

et al. 2009

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“…A key pathway regulating CD95 apoptogenic function is the one activated by PI3K/Akt. Once activated by phosphorylation, Akt is recruited at the inner leaflet of the plasma membrane and prevents the formation of plasma membrane lipid platforms containing CD95, which are fundamental to initiate apoptotic signaling (23). Ceramide inhibits Akt activation through its dephosphorylation in Ser 473 by the ceramide-activated protein phosphatase, thus potentiating the apoptotic pathway (32).…”

Section: Discussionmentioning

confidence: 99%

“…2D and supplemental Fig. 1 for representative images and Table 1 for quantitation) (23). Of importance, although both syntaxin 4 and CatD co-localized with A-SMase (see Fig.…”

Section: A-smase Translocation To the Plasma Membrane And Activation mentioning

confidence: 94%

Syntaxin 4 Is Required for Acid Sphingomyelinase Activity and Apoptotic Function

Perrotta

Bizzozero

Cazzato

et al. 2010

Journal of Biological Chemistry

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Acid sphingomyelinase (A-SMase) is an important enzyme in sphingolipid metabolism and plays key roles in apoptosis, immunity, development, and cancer. In addition, it mediates cytotoxicity of cisplatin and some other chemotherapeutic drugs. The mechanism of A-SMase activation is still undefined. We now demonstrate that, upon CD95 stimulation, ASMase is activated through translocation from intracellular compartments to the plasma membrane in an exocytic pathway requiring the t-SNARE protein syntaxin 4. Indeed, downregulation of syntaxin 4 inhibits A-SMase translocation and activation induced by CD95 stimulation. This leads to inhibition of the CD95-triggered signaling events, including caspase 3 and 9 activation and apoptosis, activation of the survival pathway involving the protein kinase Akt, and important changes in cell cycle and proliferation. The molecular interaction between A-SMase and syntaxin 4 was not known and clarifies the mechanism of A-SMase activation. The novel actions of syntaxin 4 in sphingolipid metabolism and exocytosis we describe here define signaling mechanisms of broad relevance in cell pathophysiology.Acid sphingomyelinase (A-SMase) 3 (EC 3.1.4.12) is a phosphodiesterase that catalyzes the hydrolysis of membrane lipid sphingomyelin to ceramide and phosphorylcholine. The enzyme plays important roles in pathophysiology, as it mediates the action of several apoptogenic molecules, cytokines, and neurotrophins, regulating neuronal function, immunity, and infections (1-3).Enzymatic dysfunction of A-SMase leads to Niemann-Pick diseases types A and B (4). The enzyme is also important in cancer development and therapy; tumor growth is enhanced in A-SMase knock-out mice (5), and the enzyme contributes significantly to the cytotoxic effects of several anticancer drugs (6 -9). The biology of A-SMase under resting conditions, including its localization to lysosomal compartments, has been clarified (6, 9). Less clear is how A-SMase is activated. Activation has been suggested to require translocation from intracellular compartments to the extracellular surface of the cell through pathways as yet unknown (3, 9) or to occur within the lysosomes (10). Elucidating the molecular mechanisms of A-SMase activation is of biological relevance and might reveal novel candidate targets for therapy, including cancer therapy.Using U373, a human glioma cell line expressing the death receptor CD95, we have now established that translocation of A-SMase to the plasma membrane is required for its early activation, that this process takes place by exocytosis, and that a key role in it is played by syntaxin 4, an ubiquitously expressed t-SNARE implicated in several regulated exocytic pathways including the translocation of Glut4 to the plasma membrane, exocytosis of secretory granules, and the calcium-dependent release of lysosomes (11,12). Furthermore, we demonstrate that the blockade of syntaxin 4-dependent exocytosis inhibits CD95 receptor clustering and internalization, caspase activation and loss of mitochondrial membr...

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“…To detach XIAP Recently, high activity of the lipid kinase phosphoinositide 3-kinase (PI3K) or downregulation of its neutralizing phosphatase, phosphatase and tensin homologue on chromosome 10 (PTEN), were observed in type II cells, whereas this signal is blocked in type I cell lines [79,80]. The PI3K signaling pathway prevents the aggregation of CD95 [81], probably by retaining the receptor outside of lipid rafts [79,82]. PEA-15, also known as PED, is a protein containing a death effector domain (DED) that inhibits the CD95 and TNFR1 apoptotic signals ( Figure 2) [66].…”

Section: Type I /Ii Signaling Pathwaysmentioning

confidence: 99%

The CD95/CD95L Signaling Pathway: A Role in Carcinogenesis

Fouqué

Legembre

2014

Cancer Immunology

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Apoptosis is a fundamental process that contributes to tissue homeostasis, immune responses, and development. The receptor CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance, and various lineages of malignant cells exhibit loss-offunction mutations in this pathway; therefore, CD95 was initially classified as a tumor suppressor gene. However, more recent data indicate that in different pathophysiological contexts, this receptor can transmit non-apoptotic signals, promote inflammation, and contribute to carcinogenesis. A comparison with the initial molecular events of the TNF-R signaling pathway leading to non-apoptotic, apoptotic, and necrotic pathways reveals that CD95 is probably using different molecular mechanisms to transmit its non-apoptotic signals (NF-κB, MAPK, and PI3K). As discussed in this review, the molecular process by which the receptor switches from an apoptotic function to an inflammatory role is unknown. More importantly, the biological functions of these signals remain elusive.

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Localization of Fas/CD95 into the Lipid Rafts on Down-Modulation of the Phosphatidylinositol 3-Kinase Signaling Pathway

Cited by 47 publications

References 49 publications

CD95 engagement mediates actin-independent and -dependent apoptotic signals

CD95 engagement mediates actin-independent and -dependent apoptotic signals

Syntaxin 4 Is Required for Acid Sphingomyelinase Activity and Apoptotic Function

The CD95/CD95L Signaling Pathway: A Role in Carcinogenesis

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