Chapter category: Signal Transduction
Ceramidases: Regulators of Turnover of Ceramide and Ceramide-Mediated Responses
Ceramide Signaling
Edited by: Anthony H. FutermanISBN: 0-306-47442-5
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Chapter authors:
Cungui Mao and Lina Obeid
Ceramide has been shown to mediate various stress-induced responses such as apoptosis, growth arrest, differentiation, inflammation, and heat stress response. Regulation of these responses may rely on the net cellular levels of ceramide, which are determined by a balance between the rate of its formation and that of its degradation. The formation of ceramide in response to agonists or chemotherapeutic agents appears to involve two distinct pathways, SM breakdown and de novo synthesis. The degradation of ceramide is mainly through ceramidases. Three types of ceramidase activities have been described. They are classified as acid, neutral, and alkaline types according to their pH optima for activity. Neutral and alkaline ceramidase activities appear to be regulated by growth factors, cytokines, lipoproteins, and nitric oxide (NO)- generating reagents. The mechanisms of regulation are largely unknown because the enzymes encoding the ceramidase activities have just recently been cloned. These cloned ceramidases can be divided into three groups based on sequence similarity. The first group of ceramidases including the human, mouse, and Drosophila acid ceramidases, which share significant sequence similarity, are mainly localized to lysosomes, and have pH optima of 4 to 5 for their activity. The second group of ceramidases, including the Pseudomonas and Mycobacterium alkaline ceramidases, mouse and rat brain neutral ceramidases, and human mitochondrial ceramidase, also share sequence similarity, but have broad pH optima of 7-10 and various cellular localizations. This group of ceramidases are reclassified as neutral/alkaline ceramidases. The third group of ceramidases, including the yeast alkaline phytoceramidase (YPC1p) and dihydroceramidase (YDC1p), human alkaline phytoceramidase (haPHC), and mouse alkaline ceramidase (maCER), share several conserved domains. Members of this group of enzymes have several transmembrane domains and an alkaline pH optimum, are localized to the Golgi apparatus, endoplasmic reticulum, or both, and have a more restricted substrate specificity than the first two groups of ceramidases. This group of ceramidases defines a strictly alkaline type of ceramidases. Ceramidases in one subgroup do not share any sequence similarity to those in the other subgroups although all ceramidases catalyze the same reaction, breaking down the amide linkage of ceramides. This review will focus on the cloning and characterization of these ceramidases, and their possible physiological roles.
Additional chapters from this book:
Ceramide in Serum Lipoproteins: Function and Regulation of Metabolism
Mariana N. Nikolova-Karakashian
Serum ceramide levels increase during the acute phase response to inflammation in animal models and in humans. Two major mechanisms appear to mediate these changes. The bacterial endotoxin, LP...
Crosstalk of Ceramide with Cell Survival Signaling
Toshiro Okazaki, Tadakazu Kondo, Mitsumasa Watanabe, Yoshimitsu Taguchi and Takeshi Yabu
In addition to the involvement of ceramide in pro-apoptotic signaling, the role of ceramide as an anti-apoptotic, or cell survival signal, has also been investigated. So far, many anti- apopto...
Ceramidases: Regulators of Turnover of Ceramide and Ceramide-Mediated Responses
Cungui Mao and Lina Obeid
Ceramide has been shown to mediate various stress-induced responses such as apoptosis, growth arrest, differentiation, inflammation, and heat stress response. Regulation of these responses may...
Ceramide in Apoptosis: Possible Biophysical Foundations of Action
Paavo K. J. Kinnunen and Juha M. Holopainen
One of the conserved lipid signaling systems in multicellular organisms is the SM cycle.1,2 The key molecule in this cascade is ceramide, which has been identified to serve as a sec...
Therapeutic Implications of Ceramide-Regulated Signaling Cascades
Mark Kester, Jong K. Yun, Tom Stover and Lakshman Sandirasegarane
From "Bench to Bedside" is the often-used phrase that alludes to the potential clinical or therapeutic benefits of innovative basic science research or technologies. However, the "Bench to Bed...
Ceramide in the Regulation of Neuronal Development: Two Faces of a Lipid
Christian Riebeling and Anthony H. Futerman
The notion proposed over a decade ago that ceramide is involved in cellular signaling events has stimulated a large number of studies that have attempted to define the precise function(s) of c...
Ceramide-Mediated Receptor Clustering
Erich Gulbins and Heike Grassmé
Many stress or pro-apoptotic stimuli such as irradiation, heat shock, UV light, bacterial or viral infections, ligation of CD95 or the tumor necrosis factor receptor have been shown to activat...
Molecular Evolution of Neutral Ceramidase: From Bacteria to Mammals
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Ceramidase is a hydrolase capable of cleaving the N-acyl linkage between a sphingosine base and a fatty acid of ceramide. Recent extensive studies have revealed that ceramidases can be ...
Ceramide Glycosylation and Chemotherapy Resistance
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Multidrug resistance, inherent or acquired, is a frequent characteristic of cancer cells and is difficult to predict and to manage. Multidrug resistance is caused by multiple mechanisms, including...
Kinase Suppressor of Ras as a Ceramide-Activated Protein Kinase
D. Brent Polk, Jose Lozano and Richard N. Kolesnick
Ceramide has received attention as a second messenger in a number of biological systems determining cellular proliferation, differentiation and apoptosis. Among the targets of ceramide activat...
Insights into the Modulation of Ceramide Metabolism by Naturally Occurring and Synthetic Sphingolipid Analogs as Monitored by Electrospray Tandem Mass
Alfred H. Merrill, M. Cameron Sullards, Jeremy C. Allegood, Elaine Wang, Stephen C. Linn, Lindsay Andras, Dennis C. Liotta, Michaela Hartl and Hans-Ulrich Humpf
Fumonisins have considerable structural similarity to sphinganine, as illustrated in Figure 1 for one of the most prevalent species (fumonisin B1, FB1) and its backbone amino...
The Role of Serine/Threonine Protein Phosphatases in Ceramide Signaling
Charles E. Chalfant and Yusuf A. Hannun
Sphingolipids serve as potential reservoirs for bioactive lipids and are now included with the well established mediators of signal transduction such as diacylglycerol, phosphatidylinositides,...
Neurons, Neurotrophins and Ceramide Signaling: Do Domains and Pores Contribute to the Dichotomy?
Rick T. Dobrowsky
Over the last decade, ceramide has received considerable notoriety as a lipid second messenger that mediates a variety of cell stress responses induced by numerous agonists and environmental s...
Ceramide Signaling in Cannabinoid Action
Ismael Galve-Roperh, Cristina Sánchez, Teresa Gómez del Pulgar, Guillermo Velasco, Daniel Rueda, Cristina Blázquez and Manuel Guzmán
Cannabinoids, the active components of Cannabis sativa (marijuana) and their endogenous counterparts, exert their effects by binding to specific Gi/o-protein-coupled receptors that ...
The Cross-Talk Between Nitric Oxide and Ceramide and Its Role in Apoptosis
Rico Barsacchi, Clara Sciorati and Emilio Clementi
Nitric oxide (NO), a shortlived pleiotropic messenger, is known to interact with signaling pathways operated by other messenger molecules, including ions, cyclic nucleotides, protein kinases a...
Ceramide in Apoptosis: The FAN Thesis, Not a Fantasy
Bruno Segui, Olivier Cuvillier, Sophie Malagarie-Cazenave, Sophie Levesque, Valerie Gouaze, Nathalie Andrieu-Abadie and Thierry Levade
The sphingolipid ceramide has recently been proposed as a new apoptotic cell death mediator. Here the role of the FAN (Factor Associated with Neutral sphingomyelinase activation) protein in ap...
