A Novel Cytoplasmic Domain of the p55 Tumor Necrosis Factor Receptor Initiates the Neutral Sphingomyelinase Pathway

Adam, Dieter; Wiegmann, Katja; Adam‐Klages, Sabine; Ruff, Andrea; Krönke, Martin

doi:10.1074/jbc.271.24.14617

Cited by 138 publications

(102 citation statements)

References 39 publications

(33 reference statements)

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“…These results suggest that UVA-induced apoptosis occurs through activation of acid SMase, whereas UVB-or UVC-induced apoptosis occurs through SMase-independent pathways. However, additional pathways involved in mediating UVA-induced apoptosis cannot be disregarded, including neutral SMase (25,26), stress-activated protein kinase/JNKs (12), caspases (30), and mitochondria (30), because UVA-induced apoptosis is not completely blocked in acid SMase-deficient MS1418 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The acid SMase (pH optimum 4.5-5.0) is activated in cells exposed to ionizing radiation, FAS, CD28, interleukin-1, or TNF␣ (23,24). The neutral SMase (pH optimum 7.4) has been implicated in mediating apoptosis in cells exposed to serum starvation, anti-FAS antibody, vitamin D, TNF␣, or cytosine arabinoside (25,26). Solar ultraviolet (UV) radiation is known to be one of the most common environmental carcinogens leading to skin cancer (27)(28)(29).…”

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confidence: 99%

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Involvement of the Acid Sphingomyelinase Pathway in UVA-induced Apoptosis

Zhang

Mattjus

Schmid

et al. 2001

Journal of Biological Chemistry

137

103

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The sphingomyelin-ceramide pathway is an evolutionarily conserved ubiquitous signal transduction system that regulates many cell functions including apoptosis. Sphingomyelin (SM) is hydrolyzed to ceramide by different sphingomyelinases. Ceramide serves as a second messenger in mediating cellular effects of cytokines and stress. In this study, we find that acid sphingomyelinase (SMase) activity was induced by UVA in normal JY lymphoblasts but was not detectable in MS1418 lymphoblasts from Niemann-Pick type D patients who have an inherited deficiency of acid SMase. We also provide evidence that UVA can induce apoptosis by activating acid SMase in normal JY cells. In contrast, UVA-induced apoptosis was inhibited in MS1418 cells. Exogenous SMase and its product, ceramide (10 -40 M), induced apoptosis in JY and MS1418 cells, but the substrate of SMase, SM (20 -80 M), induced apoptosis only in JY cells. These results suggest that UVA-induced apoptosis by SM is dependent on acid SMase activity. We also provide evidence that induction of apoptosis by UVA may occur through activation of JNKs via the acid SMase pathway.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Involvement of the Acid Sphingomyelinase Pathway in UVA-induced Apoptosis

Zhang

Mattjus

Schmid

et al. 2001

Journal of Biological Chemistry

137

103

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“…41 Signaling pathways mediated by the TNF 55 kDa receptor (p55) may result in an inflammatory response or the induction of apoptosis. 41,[50][51][52][53][54] To trigger the pro-inflammatory cascade, neutral SMase is coupled to p55 via the FAN protein. 52,54 Activation of apoptosis via the TNF receptor involves activation of acidic SMase through the p55 death domain.…”

Section: Ceramide Is Generated By Multiple Metabolic Pathwaysmentioning

confidence: 99%

“…41,[50][51][52][53][54] To trigger the pro-inflammatory cascade, neutral SMase is coupled to p55 via the FAN protein. 52,54 Activation of apoptosis via the TNF receptor involves activation of acidic SMase through the p55 death domain. 53 There is also evidence that neutral SMases participate in apoptotic mechanisms.…”

Section: Ceramide Is Generated By Multiple Metabolic Pathwaysmentioning

confidence: 99%

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

2001

Leukemia

167

111

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The sphingolipid ceramide is an important second signal molecule that regulates diverse signaling pathways involving apoptosis, cell senescence, the cell cycle, and differentiation. For the most part, ceramide's effects are antagonistic to growth and survival. Interestingly, ceramide and the pro-growth agonist, diacylglycerol (DAG) appear to be regulated simultaneously but in opposite directions in the sphingomyelin cycle. While ceramide stimulates signal transduction pathways that are associated with cell death or at least are inhibitory to cell growth (eg stress-activated protein kinase, SAPK, pathways), DAG activates the classical and novel isoforms of the protein kinase C (PKC) family. These PKC isoforms are associated with cell growth and cell survival.

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“…TRAF-2 links TR55 to activation of the N-terminal c-Jun kinase (JNK) cascade (20). The TR55-associated protein FAN (21) binds to a domain designated neutral sphingomyelinase activation domain (NSD) that is N-terminally adjacent to the death domain (22). FAN mediates TNF-induced activation of neutral sphingomyelinase (N-SMase) (21).…”

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confidence: 99%

Inhibition of Receptor Internalization by Monodansylcadaverine Selectively Blocks p55 Tumor Necrosis Factor Receptor Death Domain Signaling

Schütze

Machleidt

Adam

et al. 1999

Journal of Biological Chemistry

Self Cite

191

142

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The 55-kDa receptor for tumor necrosis factor (TR55) triggers multiple signaling cascades initiated by adapter proteins like TRADD and FAN. By use of the primary amine monodansylcadaverine (MDC), we addressed the functional role of tumor necrosis factor (TNF) receptor internalization for intracellular signal distribution. We show that MDC does not prevent the interaction of the p55 TNF receptor (TR55) with FAN and TRADD. Furthermore, the activation of plasmamembrane-associated neutral sphingomyelinase activation as well as the stimulation of proline-directed protein kinases were not affected in MDC-treated cells. In contrast, activation of signaling enzymes that are linked to the "death domain" of TR55, like acid sphingomyelinase and c-Jun-N-terminal protein kinase as well as TNF signaling of apoptosis in U937 and L929 cells, are blocked in the presence of MDC. The results of our study suggest a role of TR55 internalization for the activation of select TR55 death domain signaling pathways including those leading to apoptosis.Tumor necrosis factor (TNF), 1 originally defined by its antitumoral activity, is now recognized as a pleiotropic cytokine exerting a wide variety of immunoregulatory activities (for review, see Refs. 1-3). TNF action is mediated by two types of cell surface receptors of 55 kDa (TR55) and 75 kDa (TR75) molecular masses, respectively. Both receptors mediate distinct TNF responses (4 -6). The majority of activities of soluble TNF appears to be mediated by TR55 (7-11). Like other cytokine receptors, the cytoplasmic domain of both TNF receptors lacks intrinsic enzymatic activities. The activation of intracellular signaling enzyme systems is initiated by a selective interplay between the cytoplasmic domain of the TNF receptors and a number of recently identified TNF receptor-associated proteins (see Ref. Results from numerous studies have revealed that TNF signaling further involves activation of downstream enzyme systems at multiple subcellular compartments such as the plasmamembrane, endosomes, mitochondria, the cytosol, and the nucleus (for review, see Refs. 11, 23, and 24). Membrane-associated enzyme systems transmitting TR55 signals include plasmamembrane-bound phospholipases such as phosphatidylcholine-specific phospholipase C (25), which generates the lipid second messenger molecule 1,2-diacylglycerol and a N-SMase (9), producing ceramide by sphingomyelin hydrolysis. Ceramide generated at the plasmamembrane triggers activation of a 97-kDa ceramide-activated protein kinase (26), recently suggested to be identical with the "kinase suppressor of ras" (27). Ceramide-activated protein kinase belongs to a family of proline-directed protein kinases (PDPK) (9), including members of the mitogen-activated protein kinases (28). TNF signaling further involves intracellular membrane compartments like caveolae and endosomes harboring an acid SMase (A-SMase) (9,29,30). In mitochondria, TNF induces reactive oxygen species that are generated at the level of the oxidative phosphorylation complex III (31). T...

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A Novel Cytoplasmic Domain of the p55 Tumor Necrosis Factor Receptor Initiates the Neutral Sphingomyelinase Pathway

Cited by 138 publications

References 39 publications

Involvement of the Acid Sphingomyelinase Pathway in UVA-induced Apoptosis

Involvement of the Acid Sphingomyelinase Pathway in UVA-induced Apoptosis

Ceramide regulates cellular homeostasis via diverse stress signaling pathways

Inhibition of Receptor Internalization by Monodansylcadaverine Selectively Blocks p55 Tumor Necrosis Factor Receptor Death Domain Signaling

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