Neurotrophins Induce Sphingomyelin Hydrolysis

Dobrowsky, Rick T.; Jenkins, Gary M.; Hannun, Yusuf A.

doi:10.1074/jbc.270.38.22135

Cited by 276 publications

(169 citation statements)

References 68 publications

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“…Recently, it has been demonstrated that NGF activates sphingomyelinase in rat T9 anaplastic glioblastoma cells through p75 NGFR (Dobrowsky et al, 1994), indicating that ceramide may play a role in p75 NGFR signaling. Interestingly, sphingomyelinase activation was diminished in cells coexpressing the p75 NGFR receptor and trkA but was reinstated when trkA f unction was blocked (Dobrowsky et al, 1995). This is in agreement with recent observations that the trkA receptor may negatively regulate the f unctional activity of p75 NGFR (Bothwell, 1996;Van der Z ee et al, 1996).…”

supporting

confidence: 80%

Involvement of Sphingosine 1-Phosphate in Nerve Growth Factor-Mediated Neuronal Survival and Differentiation

1997

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Sphingolipid metabolites, such as ceramide and sphingosine-1-phosphate (SPP), are emerging as a new class of second messengers involved in cellular proliferation, differentiation, and apoptosis. Nerve growth factor (NGF), a neurotrophic factor for pheochromocytoma PC12 cells, induced a biphasic increase in the activity of sphingosine kinase, the enzyme that catalyzes the formation of SPP. This activation was blocked by K252a, an inhibitor of tyrosine kinase A (trkA). A rapid 1.7-fold increase was followed by a marked prolonged increase reaching a maximum of fourfold to fivefold stimulation with a concomitant increase in SPP levels and a corresponding decrease in endogenous sphingosine levels. Levels of ceramide, the precursor of sphingosine, were only slightly decreased by NGF in serumcontaining medium. However, NGF decreased the elevation of ceramide induced by serum withdrawal. Treatment of PC12 cells with SPP did not induce neurite outgrowth or neurofilament expression, yet it enhanced neurofilament expression elicited by suboptimal doses of NGF. Moreover, SPP also protected PC12 cells from apoptosis induced by serum withdrawal. To further substantiate a role for SPP in the cytoprotective actions of NGF, we found that N,N-dimethylsphingosine, a competitive inhibitor of sphingosine kinase, also induced apoptosis and interfered with the survival effect of NGF. These effects were counteracted by exogenous SPP. Moreover, other structurally related compounds, such as dihydrosphingosine 1-phosphate and lysophosphatidic acid, had no significant protective effects. Our results suggest that activation of sphingosine kinase and subsequent formation of SPP may play an important role in the differentiation and survival effects induced by NGF.

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supporting

confidence: 80%

Involvement of Sphingosine 1-Phosphate in Nerve Growth Factor-Mediated Neuronal Survival and Differentiation

1997

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“…When both TrkA and p75 receptors are co-expressed, as in the case of PC12 cells, trkA exerts a suppressive effect upon p75, as assayed by ceramide production (Dobrowsky et al, 1995). In support of this model (Figure 2), introduction of trkA receptors in PC12 cells results in a reduction of ceramide production stimulated by p75 binding to NGF.…”

Section: How P75 Signalssupporting

confidence: 61%

Neurotrophins: the biological paradox of survival factors eliciting apoptosis

Casaccia‐Bonnefil¹,

Kong²,

Chao³

1998

Cell Death Differ

123

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Neurotrophins are target-derived soluble polypeptides required for neuronal survival. Binding of neurotrophins to Trk receptor tyrosine kinases initiate signaling cascades that promote cell survival and differentiation. All family members bind to another receptor (p75 NTR ), which belongs to the tumor necrosis factor superfamily. Hence, nerve growth factor (NGF) and related trophic factors are unique in that two separate receptor types are utilized. Although the biological function of p75 NTR has been elusive, it has been suggested to mediate apoptosis of developing neurons in the absence of Trk receptors. This presents a tantalizing paradigm, in which lifedeath decisions of cells are dependent upon the expression and action of two different receptors with distinctive signaling mechanisms. In the presence of TrkA receptors, p75 can participate in the formation of high affinity binding sites and enhanced NGF responsiveness leading to a survival signal. In the absence of TrkA receptors, p75 can generate, in only specific cell populations, a death signal. Here we discuss the unique features and implications of this unusual signal transduction system.

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“…Extensive studies using these short-chain ceramides have been performed to examine the biological aspects of ceramide, revealing intracellular ceramide targets as well as various ceramide signaling pathways [51][52][53][54][55]. Importantly, recent studies also shed light on the metabolic fate of short-chain ceramides [18,22,56] (Fig.…”

Section: -3 Deacylation/reacylation Of Exogenous Short-chain Ceramidementioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

Self Cite

520

444

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Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through re-acylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

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Neurotrophins Induce Sphingomyelin Hydrolysis

Cited by 276 publications

References 68 publications

Involvement of Sphingosine 1-Phosphate in Nerve Growth Factor-Mediated Neuronal Survival and Differentiation

Involvement of Sphingosine 1-Phosphate in Nerve Growth Factor-Mediated Neuronal Survival and Differentiation

Neurotrophins: the biological paradox of survival factors eliciting apoptosis

The sphingolipid salvage pathway in ceramide metabolism and signaling

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