Skip to main content
SpringerLink
Log in

Mammalian Neutral Sphingomyelinases: Regulation and Roles in Cell Signaling Responses

  • Review Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Ceramide, a bioactive lipid, has been extensively studied and identified as an essential bioactive molecule in mediating cellular signaling pathways. Sphingomyelinase (SMase), (EC 3.1.4.12) catalyzes the cleavage of the phosphodiester bond in sphingomyelin (SM) to form ceramide and phosphocholine. In mammals, three Mg2+-dependent neutral SMases termed nSMase1, nSMase2 and nSMase3 have been identified. Among the three enzymes, nSMase2 is the most studied and has been implicated in multiple physiological responses including cell growth arrest, apoptosis, development and inflammation. In this review, we summarize recent findings for the cloned nSMases and discuss the insights for their roles in regulation ceramide metabolism and cellular signaling pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

SMase:

Sphingomyelinase

nSMase:

Neutral sphingomyelinase

SM:

Sphingomyelin

IL:

Interleukin

ER:

Endoplasmic reticulum

ROS:

Reactive oxygen species

HAE:

Human airway epithelial

TNF:

Tumor necrosis factor. GSH, glutathione

FAN:

Factor associated with N-SMase activation

VCAM:

Vascular cell adhesion molecule-1

ICAM:

Intercellular adhesion molecule-1

eNOS:

Endothelial nitric oxide synthase

LPS:

Lipopolysaccharide

IL-1β:

Interleukin 1-beta

IRAK:

IL-1β receptor-associated kinase

KO:

Knockout

PM:

Plasma membrane

AD:

Alzheimer’s disease

Aβ:

Amyloid-β peptide

References

  • Adam-Klages, S., Adam, D., Wiegmann, K., et al. (1996). FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell, 86, 937–947.

    Article  CAS  PubMed  Google Scholar 

  • Aubin, I., Adams, C. P., Opsahl, S., et al. (2005). A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nature Genetics, 37, 803–805.

    Article  CAS  PubMed  Google Scholar 

  • Bartke, N., & Hannun, Y. A. (2009). Bioactive sphingolipids: Metabolism and function. Journal of Lipid Research, 50(Suppl), S91–S96.

    Article  PubMed  Google Scholar 

  • Bernardo, K., Krut, O., Wiegmann, K., et al. (2000). Purification and characterization of a magnesium-dependent neutral sphingomyelinase from bovine brain. The Journal of Biological Chemistry, 275, 7641–7647.

    Article  CAS  PubMed  Google Scholar 

  • Birbes, H., Bawab, S. E., Obeid, L. M., & Hannun, Y. A. (2002). Mitochondria and ceramide: Intertwined roles in regulation of apoptosis. Advances in Enzyme Regulation, 42, 113–129.

    Article  CAS  PubMed  Google Scholar 

  • Chae, Y. M., Heo, S. H., Kim, J. Y., Lee, J. M., Ryoo, H. M., & Cho, J. Y. (2009). Upregulation of smpd3 via BMP2 stimulation and Runx2. BMB Reports, 42, 86–90.

    CAS  PubMed  Google Scholar 

  • Chalfant, C. E., & Spiegel, S. (2005). Sphingosine 1-phosphate and ceramide 1-phosphate: Expanding roles in cell signaling. Journal of Cell Science, 118, 4605–4612.

    Article  CAS  PubMed  Google Scholar 

  • Clarke, C. J., Guthrie, J. M., & Hannun, Y. A. (2008). Regulation of neutral sphingomyelinase-2 (nSMase2) by tumor necrosis factor-alpha involves protein kinase C-delta in lung epithelial cells. Molecular Pharmacology, 74, 1022–1032.

    Article  CAS  PubMed  Google Scholar 

  • Clarke, C. J., & Hannun, Y. A. (2006). Neutral sphingomyelinases and nSMase2: Bridging the gaps. Biochimica et Biophysica Acta, 1758, 1893–1901.

    Article  CAS  PubMed  Google Scholar 

  • Clarke, C. J., Snook, C. F., Tani, M., Matmati, N., Marchesini, N., & Hannun, Y. A. (2006). The extended family of neutral sphingomyelinases. Biochemistry, 45, 11247–11256.

    Article  CAS  PubMed  Google Scholar 

  • Clarke, C. J., Truong, T. G., & Hannun, Y. A. (2007). Role for neutral sphingomyelinase-2 in tumor necrosis factor alpha-stimulated expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM) in lung epithelial cells: p38 MAPK is an upstream regulator of nSMase2. The Journal of Biological Chemistry, 282, 1384–1396.

    Article  CAS  PubMed  Google Scholar 

  • Cogolludo, A., Moreno, L., Frazziano, G., et al. (2009). Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction. Cardiovascular Research, 82, 296–302.

    Article  CAS  PubMed  Google Scholar 

  • Coleman, D. C., Arbuthnott, J. P., Pomeroy, H. M., & Birkbeck, T. H. (1986). Cloning and expression in Escherichia coli and Staphylococcus aureus of the beta-lysin determinant from Staphylococcus aureus: Evidence that bacteriophage conversion of beta-lysin activity is caused by insertional inactivation of the beta-lysin determinant. Microbial Pathogenesis, 1, 549–564.

    Article  CAS  PubMed  Google Scholar 

  • Corcoran, C. A., He, Q., Ponnusamy, S., Ogretmen, B., Huang, Y., & Sheikh, M. S. (2008). Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Molecular Cancer Research, 6, 795–807.

    Article  CAS  PubMed  Google Scholar 

  • De Palma, C., Meacci, E., Perrotta, C., Bruni, P., & Clementi, E. (2006). Endothelial nitric oxide synthase activation by tumor necrosis factor alpha through neutral sphingomyelinase 2, sphingosine kinase 1, and sphingosine 1 phosphate receptors: A novel pathway relevant to the pathophysiology of endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 99–105.

    Article  PubMed  Google Scholar 

  • Duan, R. D. (2006). Alkaline sphingomyelinase: An old enzyme with novel implications. Biochimica et Biophysica Acta, 1761, 281–291.

    CAS  PubMed  Google Scholar 

  • El Alwani, M., Wu, B. X., Obeid, L. M., & Hannun, Y. A. (2006). Bioactive sphingolipids in the modulation of the inflammatory response. Pharmacology and Therapeutics, 112, 171–183.

    Article  CAS  PubMed  Google Scholar 

  • Fensome, A. C., Rodrigues-Lima, F., Josephs, M., Paterson, H. F., & Katan, M. (2000). A neutral magnesium-dependent sphingomyelinase isoform associated with intracellular membranes and reversibly inhibited by reactive oxygen species. The Journal of Biological Chemistry, 275, 1128–1136.

    Article  CAS  PubMed  Google Scholar 

  • Futerman, A. H. (2006). Intracellular trafficking of sphingolipids: Relationship to biosynthesis. Biochimica et Biophysica Acta, 1758, 1885–1892.

    Article  CAS  PubMed  Google Scholar 

  • Goswami, R., Ahmed, M., Kilkus, J., Han, T., Dawson, S. A., & Dawson, G. (2005). Differential regulation of ceramide in lipid-rich microdomains (rafts): Antagonistic role of palmitoyl:protein thioesterase and neutral sphingomyelinase 2. Journal of Neuroscience Research, 81, 208–217.

    Article  CAS  PubMed  Google Scholar 

  • Grimm, M. O., Grimm, H. S., Patzold, A. J., et al. (2005). Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nature Cell Biology, 7, 1118–1123.

    Article  CAS  PubMed  Google Scholar 

  • Hannun, Y. A., & Obeid, L. M. (2008). Principles of bioactive lipid signalling: Lessons from sphingolipids. Nature Reviews. Molecular Cell Biology, 9, 139–150.

    Article  CAS  PubMed  Google Scholar 

  • He, X., Huang, Y., Li, B., Gong, C. X., & Schuchman, E. H. (2008). Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiology of Aging.

  • Hofmann, K., Tomiuk, S., Wolff, G., & Stoffel, W. (2000). Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proceedings of the National Academy of Sciences of the United States of America, 97, 5895–5900.

    Article  CAS  PubMed  Google Scholar 

  • Horinouchi, K., Erlich, S., Perl, D. P., et al. (1995). Acid sphingomyelinase deficient mice: A model of types A and B Niemann-Pick disease. Nature Genetics, 10, 288–293.

    Article  CAS  PubMed  Google Scholar 

  • Ito, H., Murakami, M., Furuhata, A., et al. (2009). Transcriptional regulation of neutral sphingomyelinase 2 gene expression of a human breast cancer cell line, MCF-7, induced by the anti-cancer drug, daunorubicin. Biochimica et Biophysica Acta, 1789, 681–690.

    CAS  PubMed  Google Scholar 

  • Jana, A., Hogan, E. L., & Pahan, K. (2009). Ceramide and neurodegeneration: Susceptibility of neurons and oligodendrocytes to cell damage and death. Journal of the Neurological Science, 278, 5–15.

    Article  CAS  Google Scholar 

  • Jana, A., & Pahan, K. (2004). Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer’s disease. The Journal of Biological Chemistry, 279, 51451–51459.

    Article  CAS  PubMed  Google Scholar 

  • Jana, A., & Pahan, K. (2007). Oxidative stress kills human primary oligodendrocytes via neutral sphingomyelinase: Implications for multiple sclerosis. Journal of Neuroimmune Pharmacology, 2, 184–193.

    Article  PubMed  Google Scholar 

  • Jenkins, R. W., Canals, D., & Hannun, Y. A. (2009). Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signalling, 6, 836–846.

    Article  Google Scholar 

  • Josephs, M., Katan, M., & Rodrigues-Lima, F. (2002). Irreversible inactivation of magnesium-dependent neutral sphingomyelinase 1 (NSM1) by peroxynitrite, a nitric oxide-derived oxidant. FEBS Letters, 531, 329–334.

    Article  CAS  PubMed  Google Scholar 

  • Ju, T. C., Chen, S. D., Liu, C. C., & Yang, D. I. (2005). Protective effects of S-nitrosoglutathione against amyloid beta-peptide neurotoxicity. Free Radical Biology and Medicine, 38, 938–949.

    Article  CAS  PubMed  Google Scholar 

  • Jung, S. Y., Suh, J. H., Park, H. J., et al. (2000). Identification of multiple forms of membrane-associated neutral sphingomyelinase in bovine brain. Journal of Neurochemistry, 75, 1004–1014.

    Article  CAS  PubMed  Google Scholar 

  • Karakashian, A. A., Giltiay, N. V., Smith, G. M., & Nikolova-Karakashian, M. N. (2004). Expression of neutral sphingomyelinase-2 (NSMase-2) in primary rat hepatocytes modulates IL-beta-induced JNK activation. The Faseb Journal, 18, 968–970.

    CAS  PubMed  Google Scholar 

  • Kim, W. J., Okimoto, R. A., Purton, L. E., et al. (2008). Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood, 111, 4716–4722.

    Article  CAS  PubMed  Google Scholar 

  • Kim, R. H., Takabe, K., Milstien, S., & Spiegel, S. (2009). Export and functions of sphingosine-1-phosphate. Biochimica et Biophysica Acta, 1791, 692–696.

    CAS  PubMed  Google Scholar 

  • Kitatani, K., Idkowiak-Baldys, J., & Hannun, Y. A. (2008). The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signalling, 20, 1010–1018.

    Article  CAS  PubMed  Google Scholar 

  • Kolmakova, A., Kwiterovich, P., Virgil, D., et al. (2004). Apolipoprotein C-I induces apoptosis in human aortic smooth muscle cells via recruiting neutral sphingomyelinase. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 264–269.

    Article  CAS  PubMed  Google Scholar 

  • Krut, O., Wiegmann, K., Kashkar, H., Yazdanpanah, B., & Kronke, M. (2006). Novel tumor necrosis factor-responsive mammalian neutral sphingomyelinase-3 is a C-tail-anchored protein. The Journal of Biological Chemistry, 281, 13784–13793.

    Article  CAS  PubMed  Google Scholar 

  • Lee, J. T., Xu, J., Lee, J. M., et al. (2004). Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. The Journal of Cell Biology, 164, 123–131.

    Article  CAS  PubMed  Google Scholar 

  • Levy, M., Castillo, S. S., & Goldkorn, T. (2006). nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis. Biochemical and Biophysical Research Communications, 344, 900–905.

    Article  CAS  PubMed  Google Scholar 

  • Levy, M., Khan, E., Careaga, M., & Goldkorn, T. (2009). Neutral sphingomyelinase 2 is activated by cigarette smoke to augment ceramide-induced apoptosis in lung cell death. American Journal of Physiology Lung Cellular and Molecular Physiology, 297, L125–L133.

    Article  CAS  PubMed  Google Scholar 

  • Marchesini, N., Jones, J. A., & Hannun, Y. A. (2007). Confluence induced threonine41/serine45 phospho-beta-catenin dephosphorylation via ceramide-mediated activation of PP1cgamma. Biochimica et Biophysica Acta, 1771, 1418–1428.

    CAS  PubMed  Google Scholar 

  • Marchesini, N., Luberto, C., & Hannun, Y. A. (2003). Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism. The Journal of Biological Chemistry, 278, 13775–13783.

    Article  CAS  PubMed  Google Scholar 

  • Marchesini, N., Osta, W., Bielawski, J., Luberto, C., Obeid, L. M., & Hannun, Y. A. (2004). Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. The Journal of Biological Chemistry, 279, 25101–25111.

    Article  CAS  PubMed  Google Scholar 

  • Matmati, N., & Hannun, Y. A. (2008). Thematic review series: Sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases. Journal of Lipid Research, 49, 922–928.

    Article  CAS  PubMed  Google Scholar 

  • Milhas, D., Clarke, C. J., & Hannun, Y. A. (2009) Sphingomyelin metabolism at the plasma membrane: Implications for bioactive sphingolipids. The FEBS Letters.

  • Mizutani, Y., Tamiya-Koizumi, K., Nakamura, N., Kobayashi, M., Hirabayashi, Y., & Yoshida, S. (2001). Nuclear localization of neutral sphingomyelinase 1: Biochemical and immunocytochemical analyses. Journal of Cell Science, 114, 3727–3736.

    CAS  PubMed  Google Scholar 

  • Modrak, D. E., Gold, D. V., & Goldenberg, D. M. (2006). Sphingolipid targets in cancer therapy. Molecular Cancer Therapeutics, 5, 200–208.

    Article  CAS  PubMed  Google Scholar 

  • Morales, A., Lee, H., Goni, F. M., Kolesnick, R., & Fernandez-Checa, J. C. (2007). Sphingolipids and cell death. Apoptosis, 12, 923–939.

    Article  CAS  PubMed  Google Scholar 

  • Navas, P., Fernandez-Ayala, D. M., Martin, S. F., et al. (2002). Ceramide-dependent caspase 3 activation is prevented by coenzyme Q from plasma membrane in serum-deprived cells. Free Radical Research, 36, 369–374.

    Article  CAS  PubMed  Google Scholar 

  • Nikolova-Karakashian, M., Karakashian, A., & Rutkute, K. (2008). Role of neutral sphingomyelinases in aging and inflammation. Sub-cellular Biochemistry, 49, 469–486.

    Article  PubMed  Google Scholar 

  • Nikolova-Karakashian, M., Morgan, E. T., Alexander, C., Liotta, D. C., & Merrill, A. H., Jr. (1997). Bimodal regulation of ceramidase by interleukin-1beta. Implications for the regulation of cytochrome p450 2C11. The Journal of Biological Chemistry, 272, 18718–18724.

    Article  CAS  PubMed  Google Scholar 

  • Novgorodov, S. A., & Gudz, T. I. (2009). Ceramide and mitochondria in ischemia/reperfusion. Journal of Cardiovascular Pharmacology, 53, 198–208.

    Article  CAS  PubMed  Google Scholar 

  • Ogretmen, B., & Hannun, Y. A. (2004). Biologically active sphingolipids in cancer pathogenesis and treatment. Nature Reviews Cancer, 4, 604–616.

    Article  CAS  PubMed  Google Scholar 

  • Otterbach, B., & Stoffel, W. (1995). Acid sphingomyelinase-deficient mice mimic the neurovisceral form of human lysosomal storage disease (Niemann-Pick disease). Cell, 81, 1053–1061.

    Article  CAS  PubMed  Google Scholar 

  • Perry, D. K. (2002). Serine palmitoyltransferase: Role in apoptotic de novo ceramide synthesis and other stress responses. Biochimica et Biophysica Acta, 1585, 146–152.

    CAS  PubMed  Google Scholar 

  • Philipp, S., Puchert, M., Adam-Klages, S., et al. (2010). The Polycomb group protein EED couples TNF receptor 1 to neutral sphingomyelinase. Proceedings of the National Academy of Sciences of the United States of America, 107, 1112–1117.

    Article  CAS  PubMed  Google Scholar 

  • Puglielli, L., Ellis, B. C., Saunders, A. J., & Kovacs, D. M. (2003). Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. The Journal of Biological Chemistry, 278, 19777–19783.

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues-Lima, F., Fensome, A. C., Josephs, M., Evans, J., Veldman, R. J., & Katan, M. (2000). Structural requirements for catalysis and membrane targeting of mammalian enzymes with neutral sphingomyelinase and lysophospholipid phospholipase C activities. Analysis by chemical modification and site-directed mutagenesis. The Journal of Biological Chemistry, 275, 28316–28325.

    CAS  PubMed  Google Scholar 

  • Rutkute, K., Asmis, R. H., & Nikolova-Karakashian, M. N. (2007a). Regulation of neutral sphingomyelinase-2 by GSH: A new insight to the role of oxidative stress in aging-associated inflammation. Journal of Lipid Research, 48, 2443–2452.

    Article  CAS  PubMed  Google Scholar 

  • Rutkute, K., Karakashian, A. A., Giltiay, N. V., Dobierzewska, A., & Nikolova-Karakashian, M. N. (2007b). Aging in rat causes hepatic hyperresposiveness to interleukin-1beta which is mediated by neutral sphingomyelinase-2. Hepatology, 46, 1166–1176.

    Article  CAS  PubMed  Google Scholar 

  • Sawai, H., Domae, N., Nagan, N., & Hannun, Y. A. (1999). Function of the cloned putative neutral sphingomyelinase as lyso-platelet activating factor-phospholipase C. The Journal of Biological Chemistry, 274, 38131–38139.

    Article  CAS  PubMed  Google Scholar 

  • Sawai, H., Okamoto, Y., Luberto, C., et al. (2000). Identification of ISC1 (YER019w) as inositol phosphosphingolipid phospholipase C in Saccharomyces cerevisiae. The Journal of Biological Chemistry, 275, 39793–39798.

    Article  CAS  PubMed  Google Scholar 

  • Schneider, P. B., & Kennedy, E. P. (1967). Sphingomyelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. Journal of Lipid Research, 8, 202–209.

    CAS  PubMed  Google Scholar 

  • Schuchman, E. H. (2007). The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. Journal of Inherited Metabolic Disease, 30, 654–663.

    Article  CAS  PubMed  Google Scholar 

  • Schulze, J., Albers, J., Baranowsky, A., et al. (2009). Osteolytic prostate cancer cells induce the expression of specific cytokines in bone-forming osteoblasts through a Stat3/5-dependent mechanism. Bone.

  • Somenzi, G., Sala, G., Rossetti, S., Ren, M., Ghidoni, R., & Sacchi, N. (2007). Disruption of retinoic acid receptor alpha reveals the growth promoter face of retinoic acid. PLoS One, 2, e836.

    Article  PubMed  Google Scholar 

  • Stoffel, W. (1999). Functional analysis of acid and neutral sphingomyelinases in vitro and in vivo. Chemistry and Physics of Lipids, 102, 107–121.

    Article  CAS  PubMed  Google Scholar 

  • Stoffel, W., Jenke, B., Block, B., Zumbansen, M., & Koebke, J. (2005). Neutral sphingomyelinase 2 (smpd3) in the control of postnatal growth and development. Proceedings of the National Academy of Sciences of the United States of America, 102, 4554–4559.

    Article  CAS  PubMed  Google Scholar 

  • Stoffel, W., Jenke, B., Holz, B., et al. (2007). Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. American Journal of Pathology, 171, 153–161.

    Article  CAS  PubMed  Google Scholar 

  • Tani, M., & Hannun, Y. A. (2007a). Analysis of membrane topology of neutral sphingomyelinase 2. FEBS Letters, 581, 1323–1328.

    Article  CAS  PubMed  Google Scholar 

  • Tani, M., & Hannun, Y. A. (2007b). Neutral sphingomyelinase 2 is palmitoylated on multiple cysteine residues. Role of palmitoylation in subcellular localization. The Journal of Biological Chemistry, 282, 10047–10056.

    Article  CAS  PubMed  Google Scholar 

  • Tcherkasowa, A. E., Adam-Klages, S., Kruse, M. L., et al. (2002). Interaction with factor associated with neutral sphingomyelinase activation, a WD motif-containing protein, identifies receptor for activated C-kinase 1 as a novel component of the signaling pathways of the p55 TNF receptor. Journal of Immunology, 169, 5161–5170.

    Google Scholar 

  • Tellier, E., Negre-Salvayre, A., Bocquet, B., et al. (2007). Role for furin in tumor necrosis factor alpha-induced activation of the matrix metalloproteinase/sphingolipid mitogenic pathway. Molecular and Cellular Biology, 27, 2997–3007.

    Article  CAS  PubMed  Google Scholar 

  • Tepper, A. D., Ruurs, P., Borst, J., & van Blitterswijk, W. J. (2001). Effect of overexpression of a neutral sphingomyelinase on CD95-induced ceramide production and apoptosis. Biochemical and Biophysical Research Communications, 280, 634–639.

    Article  CAS  PubMed  Google Scholar 

  • Tomiuk, S., Hofmann, K., Nix, M., Zumbansen, M., & Stoffel, W. (1998). Cloned mammalian neutral sphingomyelinase: Functions in sphingolipid signaling? Proceedings of the National Academy of Sciences of the United States of America, 95, 3638–3643.

    Article  CAS  PubMed  Google Scholar 

  • Tomiuk, S., Zumbansen, M., & Stoffel, W. (2000). Characterization and subcellular localization of murine and human magnesium-dependent neutral sphingomyelinase. The Journal of Biological Chemistry, 275, 5710–5717.

    Article  CAS  PubMed  Google Scholar 

  • Tonnetti, L., Veri, M. C., Bonvini, E., & D’Adamio, L. (1999). A role for neutral sphingomyelinase-mediated ceramide production in T cell receptor-induced apoptosis and mitogen-activated protein kinase-mediated signal transduction. The Journal of Experimental Medicine, 189, 1581–1589.

    Article  CAS  PubMed  Google Scholar 

  • Vance, J. E., & Steenbergen, R. (2005). Metabolism and functions of phosphatidylserine. Progress in Lipid Research, 44, 207–234.

    Article  CAS  PubMed  Google Scholar 

  • Wheeler, D., Knapp, E., Bandaru, V. V., et al. (2009). Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. Journal of Neurochemistry, 109, 1237–1249.

    Article  CAS  PubMed  Google Scholar 

  • Won, J. S., Im, Y. B., Khan, M., Singh, A. K., & Singh, I. (2004). The role of neutral sphingomyelinase produced ceramide in lipopolysaccharide-mediated expression of inducible nitric oxide synthase. Journal of Neurochemistry, 88, 583–593.

    Article  CAS  PubMed  Google Scholar 

  • Yabu, T., Imamura, S., Yamashita, M., & Okazaki, T. (2008). Identification of Mg2+-dependent neutral sphingomyelinase 1 as a mediator of heat stress-induced ceramide generation and apoptosis. The Journal of Biological Chemistry, 283, 29971–29982.

    Article  CAS  PubMed  Google Scholar 

  • Yabu, T., Shimuzu, A., & Yamashita, M. (2009). A novel mitochondrial sphingomyelinase in zebrafish cells. The Journal of Biological Chemistry, 284, 20349–20363.

    Article  CAS  PubMed  Google Scholar 

  • Yamada, A., Tsukagoshi, N., Udaka, S., et al. (1988). Nucleotide sequence and expression in Escherichia coli of the gene coding for sphingomyelinase of Bacillus cereus. European Journal of Biochemistry, 175, 213–220.

    Article  CAS  PubMed  Google Scholar 

  • Yang, D. I., Yeh, C. H., Chen, S., Xu, J., & Hsu, C. Y. (2004). Neutral sphingomyelinase activation in endothelial and glial cell death induced by amyloid beta-peptide. Neurobiology of Disease, 17, 99–107.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, W., Kollmeyer, J., Symolon, H., et al. (2006). Ceramides and other bioactive sphingolipid backbones in health and disease: Lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy. Biochimica et Biophysica Acta, 1758, 1864–1884.

    Article  CAS  PubMed  Google Scholar 

  • Zumbansen, M., & Stoffel, W. (2002). Neutral sphingomyelinase 1 deficiency in the mouse causes no lipid storage disease. Molecular and Cellular Biology, 22, 3633–3638.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by NIH grant GM43825.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC, 29425, USA

    Bill X. Wu, Christopher J. Clarke & Yusuf A. Hannun

Authors
  1. Bill X. Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher J. Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yusuf A. Hannun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusuf A. Hannun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, B.X., Clarke, C.J. & Hannun, Y.A. Mammalian Neutral Sphingomyelinases: Regulation and Roles in Cell Signaling Responses. Neuromol Med 12, 320–330 (2010). https://doi.org/10.1007/s12017-010-8120-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-010-8120-z

Keywords

Search

Navigation