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Sphingolipids: Basic Science and Drug Development pp 57–76Cite as

Sphingolipid Metabolism and Neutral Sphingomyelinases

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 215))

Abstract

Sphingolipids are an important class of lipid molecules that play fundamental roles in our cells and body. Beyond a structural role, it is now clearly established that sphingolipids serve as bioactive signaling molecules to regulate diverse processes including inflammatory signaling, cell death, proliferation, and pain sensing. Sphingolipid metabolites have been implicated in the onset and progression of various diseases including cancer, lung disease, diabetes, and lysosomal storage disorders. Here we review sphingolipid metabolism to introduce basic concepts as well as emerging complexities in sphingolipid function gained from modern technological advances and detailed cell and animal studies. Furthermore, we discuss the family of neutral sphingomyelinases (N-SMases), which generate ceramide through the hydrolysis of sphingomyelin and are key enzymes in sphingolipid metabolism. Four mammalian N-SMase enzymes have now been identified. Most prominent is nSMase2 with established roles in bone mineralization, exosome formation, and cellular stress responses. Function for the other N-SMases has been more enigmatic and is an area of active investigation. The known properties and potential role(s) of each enzyme are discussed to help guide future studies.

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References

  • Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J, Kronke M (1996) FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell 86(6):937–947, S0092-8674(00)80169-5 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Ago H, Oda M, Takahashi M, Tsuge H, Ochi S, Katunuma N, Miyano M, Sakurai J (2006) Structural basis of the sphingomyelin phosphodiesterase activity in neutral sphingomyelinase from Bacillus cereus. J Biol Chem 281(23):16157–16167. doi:10.1074/jbc.M601089200, M601089200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Arana L, Gangoiti P, Ouro A, Trueba M, Gómez-Muñoz A (2010) Ceramide and ceramide 1-phosphate in health and disease. Lipids Health Dis 9:15

    Article  PubMed  Google Scholar 

  • Aubin I, Adams CP, Opsahl S, Septier D, Bishop CE, Auge N, Salvayre R, Negre-Salvayre A, Goldberg M, Guenet JL, Poirier C (2005) A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nat Genet 37(8):803–805. doi:10.1038/ng1603, ng1603 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50(Suppl):S91–S96. doi:10.1194/jlr.R800080-JLR200, R800080-JLR200 [pii]

    Article  PubMed  Google Scholar 

  • Ben-David O, Futerman AH (2010) The role of the ceramide acyl chain length in neurodegeneration: involvement of ceramide synthases. Neuromolecular Med 12(4):341–350

    Article  PubMed  CAS  Google Scholar 

  • Bernardo K, Krut O, Wiegmann K, Kreder D, Micheli M, Schafer R, Sickman A, Schmidt WE, Schroder JM, Meyer HE, Sandhoff K, Kronke M (2000) Purification and characterization of a magnesium-dependent neutral sphingomyelinase from bovine brain. J Biol Chem 275(11):7641–7647

    Article  PubMed  CAS  Google Scholar 

  • Canals D, Perry DM, Jenkins RW, Hannun YA (2011) Drug targeting of sphingolipid metabolism: sphingomyelinases and ceramidases. Br J Pharmacol 163(4):694–712. doi:10.1111/j.1476-5381.2011.01279.x

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Liang H, Zhang J, Zen K, Zhang CY (2012) Secreted microRNAs: a new form of intercellular communication. Trends Cell Biol 22:125–132

    Article  PubMed  CAS  Google Scholar 

  • Clarke CJ, Snook CF, Tani M, Matmati N, Marchesini N, Hannun YA (2006) The extended family of neutral sphingomyelinases. Biochemistry 45(38):11247–11256. doi:10.1021/bi061307z

    Article  PubMed  CAS  Google Scholar 

  • Clarke CJ, Truong TG, Hannun YA (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. J Biol Chem 282(2):1384–1396. doi:10.1074/jbc.M609216200, M609216200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Clarke CJ, Guthrie JM, Hannun YA (2008) Regulation of neutral sphingomyelinase-2 (nSMase2) by tumor necrosis factor-alpha involves protein kinase C-delta in lung epithelial cells. Mol Pharmacol 74(4):1022–1032. doi:10.1124/mol.108.046250, mol.108.046250 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Clarke CJ, Wu BX, Hannun YA (2011a) The neutral sphingomyelinase family: identifying biochemical connections. Adv Enzyme Regul 51(1):51–58. doi:10.1016/j.advenzreg.2010.09.016, S0065-2571(10)00075-0 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Clarke CJ, Mediwala K, Jenkins RW, Sutton CA, Tholanikunnel BG, Hannun YA (2011b) Neutral sphingomyelinase-2 mediates growth arrest by retinoic acid through modulation of ribosomal S6 kinase. J Biol Chem 286(24):21565–21576. doi:10.1074/jbc.M110.193375, M110.193375 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Clarke CJ, Cloessner EA, Roddy PL, Hannun YA (2011c) Neutral sphingomyelinase 2 (nSMase2) is the primary neutral sphingomyelinase isoform activated by tumour necrosis factor-alpha in MCF-7 cells. Biochem J 435(2):381–390. doi:10.1042/BJ20101752, BJ20101752 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Corcoran CA, He Q, Ponnusamy S, Ogretmen B, Huang Y, Sheikh MS (2008) Neutral sphingomyelinase-3 is a DNA damage and nongenotoxic stress-regulated gene that is deregulated in human malignancies. Mol Cancer Res 6(5):795–807. doi:10.1158/1541-7786.MCR-07-2097, 6/5/795 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Devillard R, Galvani S, Thiers JC, Guenet JL, Hannun Y, Bielawski J, Negre-Salvayre A, Salvayre R, Auge N (2010) Stress-induced sphingolipid signaling: role of type-2 neutral sphingomyelinase in murine cell apoptosis and proliferation. PLoS One 5(3):e9826. doi:10.1371/journal.pone.0009826

    Article  PubMed  Google Scholar 

  • Filosto S, Fry W, Knowlton AA, Goldkorn T (2010) Neutral sphingomyelinase 2 (nSMase2) is a phosphoprotein regulated by calcineurin (PP2B). J Biol Chem 285(14):10213–10222. doi:10.1074/jbc.M109.069963, M109.069963 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Filosto S, Castillo S, Danielson A, Franzi L, Khan E, Kenyon N, Last J, Pinkerton K, Tuder R, Goldkorn T (2011) Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury. Am J Respir Cell Mol Biol 44(3):350–360. doi:10.1165/rcmb.2009-0422OC, 2009-0422OC [pii]

    Article  PubMed  CAS  Google Scholar 

  • Filosto S, Ashfaq M, Chung S, Fry W, Goldkorn T (2012) Neutral sphingomyelinase 2 activity and protein stability are modulated by phosphorylation of five conserved serines. J Biol Chem 287:514–522. doi:10.1074/jbc.M111.315481, M111.315481 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Gault CR, Obeid LM, Hannun YA (2010) An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 688:1–23

    Article  PubMed  CAS  Google Scholar 

  • Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R (2002) Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 17(1):30–38. doi:10.1359/jbmr.2002.17.1.30

    Article  PubMed  Google Scholar 

  • Goldkorn T, Filosto S (2010) Lung injury and cancer: mechanistic insights into ceramide and EGFR signaling under cigarette smoke. Am J Respir Cell Mol Biol 43(3):259

    Article  PubMed  CAS  Google Scholar 

  • Grosch S, Schiffmann S, Geisslinger G (2012) Chain length-specific properties of ceramides. Prog Lipid Res 51(1):50–62. doi:10.1016/j.plipres.2011.11.001, S0163-7827(11)00042-7 [pii]

    Article  PubMed  Google Scholar 

  • Hama H (2010) Fatty acid 2-hydroxylation in mammalian sphingolipid biology. Biochim Biophys Acta 1801(4):405–414

    Article  PubMed  CAS  Google Scholar 

  • Han G, Gupta SD, Gable K, Niranjanakumari S, Moitra P, Eichler F, Brown RH, Harmon JM, Dunn TM (2009) Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci 106(20):8186

    Article  PubMed  CAS  Google Scholar 

  • Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9(2):139–150. doi:10.1038/nrm2329, nrm2329 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Hannun YA, Obeid LM (2011) Many ceramides. J Biol Chem 286(32):27855–27862. doi:10.1074/jbc.R111.254359, R111.254359 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Hayashi Y, Kiyono T, Fujita M, Ishibashi M (1997) cca1 is required for formation of growth-arrested confluent monolayer of rat 3Y1 cells. J Biol Chem 272(29):18082–18086

    Article  PubMed  CAS  Google Scholar 

  • Hofmann K, Tomiuk S, Wolff G, Stoffel W (2000) Cloning and characterization of the mammalian brain-specific, Mg2 + -dependent neutral sphingomyelinase. Proc Natl Acad Sci U S A 97(11):5895–5900, 97/11/5895 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Hu W, Xu R, Sun W, Szulc ZM, Bielawski J, Obeid LM, Mao C (2010) Alkaline ceramidase 3 (ACER3) hydrolyzes unsaturated long-chain ceramides, and its down-regulation inhibits both cell proliferation and apoptosis. J Biol Chem 285(11):7964–7976. doi:10.1074/jbc.M109.063586, M109.063586 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Ito H, Murakami M, Furuhata A, Gao S, Yoshida K, Sobue S, Hagiwara K, Takagi A, Kojima T, Suzuki M, Banno Y, Tanaka K, Tamiya-Koizumi K, Kyogashima M, Nozawa Y, Murate T (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. Biochim Biophys Acta 1789(11–12):681–690. doi:10.1016/j.bbagrm.2009.08.006, S1874-9399(09)00100-X [pii]

    PubMed  CAS  Google Scholar 

  • Jenkins RW, Canals D, Hannun YA (2009) Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal 21(6):836–846

    Article  PubMed  CAS  Google Scholar 

  • Khavandgar Z, Poirier C, Clarke CJ, Li J, Wang N, McKee MD, Hannun YA, Murshed M (2011) A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization. J Cell Biol 194(2):277–289. doi:10.1083/jcb.201102051, jcb.201102051 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Kim WJ, Okimoto RA, Purton LE, Goodwin M, Haserlat SM, Dayyani F, Sweetser DA, McClatchey AI, Bernard OA, Look AT, Bell DW, Scadden DT, Haber DA (2008) Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood 111(9):4716–4722. doi:10.1182/blood-2007-10-113068, blood-2007-10-113068 [pii]

    Article  PubMed  CAS  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. J Biol Chem 281(19):13784–13793. doi:10.1074/jbc.M511306200, M511306200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Leventis PA, Grinstein S (2010) The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 39:407–427. doi:10.1146/annurev.biophys.093008.131234

    Article  PubMed  CAS  Google Scholar 

  • Levy M, Castillo SS, Goldkorn T (2006) nSMase2 activation and trafficking are modulated by oxidative stress to induce apoptosis. Biochem Biophys Res Commun 344(3):900–905. doi:10.1016/j.bbrc.2006.04.013, S0006-291X(06)00788-1 [pii]

    Article  PubMed  CAS  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. Am J Physiol Lung Cell Mol Physiol 297(1):L125–L133. doi:10.1152/ajplung.00031.2009, 00031.2009 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Long JZ, Cisar JS, Milliken D, Niessen S, Wang C, Trauger SA, Siuzdak G, Cravatt BF (2011) Metabolomics annotates ABHD3 as a physiologic regulator of medium-chain phospholipids. Nat Chem Biol 7(11):763–765. doi:10.1038/nchembio.659, nchembio.659 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Luberto C, Hassler DF, Signorelli P, Okamoto Y, Sawai H, Boros E, Hazen-Martin DJ, Obeid LM, Hannun YA, Smith GK (2002) Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. J Biol Chem 277(43):41128–41139. doi:10.1074/jbc.M206747200, M206747200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Mao C, Obeid LM (2008) Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim Biophys Acta 1781(9):424–434

    Article  PubMed  CAS  Google Scholar 

  • Marchesini N, Osta W, Bielawski J, Luberto C, Obeid LM, Hannun YA (2004) Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. J Biol Chem 279(24):25101–25111. doi:10.1074/jbc.M313662200, M313662200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Matmati N, Hannun YA (2008) Thematic review series: sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases. J Lipid Res 49(5):922–928. doi:10.1194/jlr.R800004-JLR200, R800004-JLR200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111(10):6387

    Article  PubMed  CAS  Google Scholar 

  • Mesicek J, Lee H, Feldman T, Jiang X, Skobeleva A, Berdyshev EV, Haimovitz-Friedman A, Fuks Z, Kolesnick R (2010) Ceramide synthases 2, 5, and 6 confer distinct roles in radiation-induced apoptosis in HeLa cells. Cell Signal 22(9):1300–1307

    Article  PubMed  CAS  Google Scholar 

  • Milhas D, Clarke CJ, Hannun YA (2010a) Sphingomyelin metabolism at the plasma membrane: implications for bioactive sphingolipids. FEBS Lett 584(9):1887–1894. doi:10.1016/j.febslet.2009.10.058, S0014-5793(09)00846-1 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Milhas D, Clarke CJ, Idkowiak-Baldys J, Canals D, Hannun YA (2010b) Anterograde and retrograde transport of neutral sphingomyelinase-2 between the Golgi and the plasma membrane. Biochim Biophys Acta 1801(12):1361–1374. doi:10.1016/j.bbalip.2010.08.001, S1388-1981(10)00179-4 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Mizutani Y, Tamiya-Koizumi K, Nakamura N, Kobayashi M, Hirabayashi Y, Yoshida S (2001) Nuclear localization of neutral sphingomyelinase 1: biochemical and immunocytochemical analyses. J Cell Sci 114(Pt 20):3727–3736

    PubMed  CAS  Google Scholar 

  • Mullen TD, Obeid LM (2012) Ceramide and apoptosis: exploring the enigmatic connections between sphingolipid metabolism and programmed cell death. Anticancer Agents Med Chem 12:340–363, BSP/ACAMC/E-Pub/00187 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Mullen TD, Jenkins RW, Clarke CJ, Bielawski J, Hannun YA, Obeid LM (2011) Ceramide synthase-dependent ceramide generation and programmed cell death. J Biol Chem 286(18):15929

    Article  PubMed  CAS  Google Scholar 

  • Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441(3):789–802. doi:10.1042/BJ20111626, BJ20111626 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Nikolova-Karakashian M, Karakashian A, Rutkute K (2008) Role of neutral sphingomyelinases in aging and inflammation. Subcell Biochem 49:469–486. doi:10.1007/978-1-4020-8831-5_18

    Article  PubMed  Google Scholar 

  • Okamoto Y, Vaena de Avalos S, Hannun YA (2003) Functional analysis of ISC1 by site-directed mutagenesis. Biochemistry 42(25):7855–7862. doi:10.1021/bi0341354

    Article  PubMed  CAS  Google Scholar 

  • Openshaw AE, Race PR, Monzo HJ, Vazquez-Boland JA, Banfield MJ (2005) Crystal structure of SmcL, a bacterial neutral sphingomyelinase C from Listeria. J Biol Chem 280(41):35011–35017. doi:10.1074/jbc.M506800200, M506800200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Patti GJ, Yanes O, Shriver LP, Courade JP, Tautenhahn R, Manchester M, Siuzdak G (2012) Metabolomics implicates altered sphingolipids in chronic pain of neuropathic origin. Nat Chem Biol 8(3):232–234. doi:10.1038/nchembio.767, nchembio.767 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Petcoff DW, Holland WL, Stith BJ (2008) Lipid levels in sperm, eggs, and during fertilization in Xenopus laevis. J Lipid Res 49(11):2365–2378. doi:10.1194/jlr.M800159-JLR200, M800159-JLR200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Pewzner-Jung Y, Ben-Dor S, Futerman AH (2006) When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: insights into the regulation of ceramide synthesis. J Biol Chem 281(35):25001–25005. doi:10.1074/jbc.R600010200, R600010200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Philipp S, Puchert M, Adam-Klages S, Tchikov V, Winoto-Morbach S, Mathieu S, Deerberg A, Kolker L, Marchesini N, Kabelitz D, Hannun YA, Schutze S, Adam D (2010) The Polycomb group protein EED couples TNF receptor 1 to neutral sphingomyelinase. Proc Natl Acad Sci U S A 107(3):1112–1117. doi:10.1073/pnas.0908486107, 0908486107 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Pitson SM (2011) Regulation of sphingosine kinase and sphingolipid signaling. Trends Biochem Sci 36(2):97–107

    Article  PubMed  CAS  Google Scholar 

  • Pruett ST, Bushnev A, Hagedorn K, Adiga M, Haynes CA, Sullards MC, Liotta DC, Merrill AH Jr (2008) Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols. J Lipid Res 49(8):1621–1639. doi:10.1194/jlr.R800012-JLR200, R800012-JLR200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Qin J, Berdyshev E, Poirier C, Schwartz NB, Dawson G (2012) Neutral sphingomyelinase 2 deficiency increases hyaluronan synthesis by up-regulation of hyaluronan Synthase 2 through decreased ceramide production and activation of Akt. J Biol Chem 287:13620–13632. doi:10.1074/jbc.M111.304857, M111.304857 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Sawai H, Domae N, Nagan N, Hannun YA (1999) Function of the cloned putative neutral sphingomyelinase as lyso-platelet activating factor-phospholipase C. J Biol Chem 274(53):38131–38139

    Article  PubMed  CAS  Google Scholar 

  • Schiffmann S, Ziebell S, Sandner J, Birod K, Deckmann K, Hartmann D, Rode S, Schmidt H, Angioni C, Geisslinger G (2010) Activation of ceramide synthase 6 by celecoxib leads to a selective induction of C16: 0-ceramide. Biochem Pharmacol 80(11):1632–1640

    Article  PubMed  CAS  Google Scholar 

  • Schneider PB, Kennedy EP (1967) Sphingomyelinase in normal human spleens and in spleens from subjects with Niemann-Pick disease. J Lipid Res 8(3):202–209

    PubMed  CAS  Google Scholar 

  • Serra M, Saba JD (2010) Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function. Adv Enzyme Regul 50(1):349

    Article  PubMed  Google Scholar 

  • Stace CL, Ktistakis NT (2006) Phosphatidic acid- and phosphatidylserine-binding proteins. Biochim Biophys Acta 1761(8):913–926. doi:10.1016/j.bbalip.2006.03.006, S1388-1981(06)00067-9 [pii]

    Article  PubMed  CAS  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. Proc Natl Acad Sci U S A 102(12):4554–4559. doi:10.1073/pnas.0406380102, 0406380102 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Stoffel W, Jenke B, Holz B, Binczek E, Gunter RH, Knifka J, Koebke J, Niehoff A (2007) Neutral sphingomyelinase (SMPD3) deficiency causes a novel form of chondrodysplasia and dwarfism that is rescued by Col2A1-driven smpd3 transgene expression. Am J Pathol 171(1):153–161. doi:10.2353/ajpath.2007.061285, S0002-9440(10)61951-7 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Sun W, Jin J, Xu R, Hu W, Szulc ZM, Bielawski J, Obeid LM, Mao C (2010) Substrate specificity, membrane topology, and activity regulation of human alkaline ceramidase 2 (ACER2). J Biol Chem 285(12):8995–9007. doi:10.1074/jbc.M109.069203, M109.069203 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Tani M, Hannun YA (2007a) Analysis of membrane topology of neutral sphingomyelinase 2. FEBS Lett 581(7):1323–1328. doi:10.1016/j.febslet.2007.02.046, S0014-5793(07)00214-1 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Tani M, Hannun YA (2007b) Neutral sphingomyelinase 2 is palmitoylated on multiple cysteine residues. Role of palmitoylation in subcellular localization. J Biol Chem 282(13):10047–10056. doi:10.1074/jbc.M611249200, M611249200 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Tomiuk S, Hofmann K, Nix M, Zumbansen M, Stoffel W (1998) Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proc Natl Acad Sci U S A 95(7):3638–3643

    Article  PubMed  CAS  Google Scholar 

  • Tomiuk S, Zumbansen M, Stoffel W (2000) Characterization and subcellular localization of murine and human magnesium-dependent neutral sphingomyelinase. J Biol Chem 275(8):5710–5717

    Article  PubMed  CAS  Google Scholar 

  • Wu BX, Rajagopalan V, Roddy PL, Clarke CJ, Hannun YA (2010a) Identification and characterization of murine mitochondria-associated neutral sphingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5. J Biol Chem 285(23):17993–18002. doi:10.1074/jbc.M110.102988, M110.102988 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Wu BX, Clarke CJ, Hannun YA (2010b) Mammalian neutral sphingomyelinases: regulation and roles in cell signaling responses. Neuromolecular Med 12(4):320–330. doi:10.1007/s12017-010-8120-z

    Article  PubMed  Google Scholar 

  • Wu BX, Clarke CJ, Matmati N, Montefusco D, Bartke N, Hannun YA (2011) Identification of novel anionic phospholipid binding domains in neutral sphingomyelinase 2 with selective binding preference. J Biol Chem 286(25):22362–22371. doi:10.1074/jbc.M110.156471, M110.156471 [pii]

    Article  PubMed  CAS  Google Scholar 

  • Yabu T, Shimuzu A, Yamashita M (2009) A novel mitochondrial sphingomyelinase in zebrafish cells. J Biol Chem 284(30):20349–20363. doi:10.1074/jbc.M109.004580, M109.004580 [pii]

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the NIH grant R37GM43825 (Y.A.H.) and NIH NIGMS 1F32GM100679 (MVA). We thank Chris J. Clarke, Bill X. Wu, and David M. Perry for helpful review of this manuscript.

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  1. Department of Medicine, Stony Brook University Cancer Center, Stony Brook University, Health Science Center, L-4, 178, Stony Brook, NY, 11794, USA

    Michael V. Airola & Yusuf A. Hannun

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  1. Michael V. Airola
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  2. Yusuf A. Hannun
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Correspondence to Yusuf A. Hannun .

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  1. , Department of Molecular Biology, University of Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany

    Erich Gulbins

  2. Division of Pulmonary, Allergy, Critical, Department of Medicine, Indiana University School of Medicine, W. Walnut Street 980, Indianapolis, 46202, Indiana, USA

    Irina Petrache

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Airola, M.V., Hannun, Y.A. (2013). Sphingolipid Metabolism and Neutral Sphingomyelinases. In: Gulbins, E., Petrache, I. (eds) Sphingolipids: Basic Science and Drug Development. Handbook of Experimental Pharmacology, vol 215. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1368-4_3

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