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Gene Review

Smpd2  -  sphingomyelin phosphodiesterase 2, neutral

Mus musculus

Synonyms: AW108287, Lyso-PAF-PLC, Lyso-platelet-activating factor-phospholipase C, N-SMase, Neutral sphingomyelinase, ...
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Disease relevance of Smpd2


High impact information on Smpd2


Biological context of Smpd2

  • TNF signaling is mediated by acid and neutral sphingomyelinases (A- and N-SMase), which generate ceramide, an important regulator of proliferation, differentiation, and apoptosis [10].
  • TNF-receptor I defective in internalization allows for cell death through activation of neutral sphingomyelinase [11].
  • The nSMase 1-deficient mice show an inconspicuous phenotype and no accumulation or changed metabolism of sphingomyelin or other lipids, despite grossly reduced nSMase activity in all organs except brain [12].
  • Expression of enzymes involved in ceramide generation (neutral sphingomyelinase [NSMase], acid sphingomyelinase [ASMase], and serine-palmitoyl-transferase [SPT]) and ceramide hydrolysis (ceramidase) are elevated in obese adipose tissues [13].
  • Introduction of single mutations into either of the histidine residues at positions 136 and 272, putative active sites, entirely abolished the activity, supporting a common mechanism for the nSMase family independent of the species [1].

Anatomical context of Smpd2

  • We report here the cloning, identification, and functional characterization of murine and human nSMase, a ubiquitously expressed integral membrane protein, which displays all established properties of the Mg2+-dependent nSMase of the plasma membrane [9].
  • Stably nSMase-overexpressing U937 and human embryonic kidney cell lines have been generated for the study of the role of nSMase in signal transduction pathways [9].
  • On the other hand, during cancer and endothelial cell interaction, t-PTER- and QUER-induced NO release from the vascular endothelium up-regulated neutral sphingomyelinase activity and ceramide generation in B16M-F10 cells [14].
  • Treating PCC7-Mz1 stem cells with a neutral sphingomyelinase or with the ceramidase inhibitor N-oleoylethanolamine elevated the endogenous ceramide levels and concomitantly induced apoptosis [15].
  • Short-term stimulation of mesangial cells with the pro-inflammatory cytokine interleukin-1beta (IL-1beta) leads to a rapid and transient increase in neutral sphingomyelinase activity (Kaszkin, M., Huwiler, A., Scholz, K., van den Bosch, H., and Pfeilschifter, J. (1998) FEBS Lett. 440, 163-166) [16].

Associations of Smpd2 with chemical compounds


Regulatory relationships of Smpd2


Other interactions of Smpd2


Analytical, diagnostic and therapeutic context of Smpd2


  1. Cloning and expression of rat neutral sphingomyelinase: enzymological characterization and identification of essential histidine residues. Mizutani, Y., Tamiya-Koizumi, K., Irie, F., Hirabayashi, Y., Miwa, M., Yoshida, S. Biochim. Biophys. Acta (2000) [Pubmed]
  2. Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis. Chmura, S.J., Nodzenski, E., Kharbanda, S., Pandey, P., Quintans, J., Kufe, D.W., Weichselbaum, R.R. Mol. Pharmacol. (2000) [Pubmed]
  3. Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway. Wu, M., Harvey, K.A., Ruzmetov, N., Welch, Z.R., Sech, L., Jackson, K., Stillwell, W., Zaloga, G.P., Siddiqui, R.A. Int. J. Cancer (2005) [Pubmed]
  4. Ceramide triggers p53-dependent apoptosis in genetically defined fibrosarcoma tumour cells. Pruschy, M., Resch, H., Shi, Y.Q., Aalame, N., Glanzmann, C., Bodis, S. Br. J. Cancer (1999) [Pubmed]
  5. Factor associated with neutral sphingomyelinase activation and its role in cardiac cell death. O'Brien, N.W., Gellings, N.M., Guo, M., Barlow, S.B., Glembotski, C.C., Sabbadini, R.A. Circ. Res. (2003) [Pubmed]
  6. Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Wiegmann, K., Schütze, S., Machleidt, T., Witte, D., Krönke, M. Cell (1994) [Pubmed]
  7. Involvement of FAN in TNF-induced apoptosis. Ségui, B., Cuvillier, O., Adam-Klages, S., Garcia, V., Malagarie-Cazenave, S., Lévêque, S., Caspar-Bauguil, S., Coudert, J., Salvayre, R., Krönke, M., Levade, T. J. Clin. Invest. (2001) [Pubmed]
  8. Impaired neutral sphingomyelinase activation and cutaneous barrier repair in FAN-deficient mice. Kreder, D., Krut, O., Adam-Klages, S., Wiegmann, K., Scherer, G., Plitz, T., Jensen, J.M., Proksch, E., Steinmann, J., Pfeffer, K., Krönke, M. EMBO J. (1999) [Pubmed]
  9. Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Tomiuk, S., Hofmann, K., Nix, M., Zumbansen, M., Stoffel, W. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  10. Roles for tumor necrosis factor receptor p55 and sphingomyelinase in repairing the cutaneous permeability barrier. Jensen, J.M., Schütze, S., Förl, M., Krönke, M., Proksch, E. J. Clin. Invest. (1999) [Pubmed]
  11. TNF-receptor I defective in internalization allows for cell death through activation of neutral sphingomyelinase. Neumeyer, J., Hallas, C., Merkel, O., Winoto-Morbach, S., Jakob, M., Thon, L., Adam, D., Schneider-Brachert, W., Schütze, S. Exp. Cell Res. (2006) [Pubmed]
  12. Neutral sphingomyelinase 1 deficiency in the mouse causes no lipid storage disease. Zumbansen, M., Stoffel, W. Mol. Cell. Biol. (2002) [Pubmed]
  13. Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Samad, F., Hester, K.D., Yang, G., Hannun, Y.A., Bielawski, J. Diabetes (2006) [Pubmed]
  14. Nitric Oxide Mediates Natural Polyphenol-induced Bcl-2 Down-regulation and Activation of Cell Death in Metastatic B16 Melanoma. Ferrer, P., Asensi, M., Priego, S., Benlloch, M., Mena, S., Ortega, A., Obrador, E., Esteve, J.M., Estrela, J.M. J. Biol. Chem. (2007) [Pubmed]
  15. Production of ceramides causes apoptosis during early neural differentiation in vitro. Herget, T., Esdar, C., Oehrlein, S.A., Heinrich, M., Schütze, S., Maelicke, A., van Echten-Deckert, G. J. Biol. Chem. (2000) [Pubmed]
  16. Interleukin-1beta induces chronic activation and de novo synthesis of neutral ceramidase in renal mesangial cells. Franzen, R., Pautz, A., Bräutigam, L., Geisslinger, G., Pfeilschifter, J., Huwiler, A. J. Biol. Chem. (2001) [Pubmed]
  17. Acid and neutral sphingomyelinase, ceramide synthase, and acid ceramidase activities in cutaneous aging. Jensen, J.M., Förl, M., Winoto-Morbach, S., Seite, S., Schunck, M., Proksch, E., Schütze, S. Exp. Dermatol. (2005) [Pubmed]
  18. A mediator role of ceramide in the regulation of neuroblastoma Neuro2a cell differentiation. Riboni, L., Prinetti, A., Bassi, R., Caminiti, A., Tettamanti, G. J. Biol. Chem. (1995) [Pubmed]
  19. Irreversible inactivation of magnesium-dependent neutral sphingomyelinase 1 (NSM1) by peroxynitrite, a nitric oxide-derived oxidant. Josephs, M., Katan, M., Rodrigues-Lima, F. FEBS Lett. (2002) [Pubmed]
  20. Activation of ERK1/2 and cPLA(2) by the p55 TNF receptor occurs independently of FAN. Lüschen, S., Adam, D., Ussat, S., Kreder, D., Schneider-Brachert, W., Krönke, M., Adam-Klages, S. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  21. Myelin contains neutral sphingomyelinase activity that is stimulated by tumor necrosis factor-alpha. Chakraborty, G., Ziemba, S., Drivas, A., Ledeen, R.W. J. Neurosci. Res. (1997) [Pubmed]
  22. The CD40-ligand stimulates T-lymphocytes via the neutral sphingomyelinase: a novel function of the CD40-ligand as signalling molecule. Koppenhoefer, U., Brenner, B., Lang, F., Gulbins, E. FEBS Lett. (1997) [Pubmed]
  23. A novel cytoplasmic domain of the p55 tumor necrosis factor receptor initiates the neutral sphingomyelinase pathway. Adam, D., Wiegmann, K., Adam-Klages, S., Ruff, A., Krönke, M. J. Biol. Chem. (1996) [Pubmed]
  24. TNF-alpha-mediated lysosomal permeabilization is FAN and caspase 8/Bid dependent. Werneburg, N., Guicciardi, M.E., Yin, X.M., Gores, G.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  25. Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TrkA and requires the common neurotrophin receptor P75. Culmsee, C., Gerling, N., Lehmann, M., Nikolova-Karakashian, M., Prehn, J.H., Mattson, M.P., Krieglstein, J. Neuroscience (2002) [Pubmed]
  26. Evidence that neutral sphingomyelinase of cultured murine neuroblastoma cells is oriented externally on the plasma membrane. Das, D.V., Cook, H.W., Spence, M.W. Biochim. Biophys. Acta (1984) [Pubmed]
  27. 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. Rodrigues-Lima, F., Fensome, A.C., Josephs, M., Evans, J., Veldman, R.J., Katan, M. J. Biol. Chem. (2000) [Pubmed]
  28. Characterization and subcellular localization of murine and human magnesium-dependent neutral sphingomyelinase. Tomiuk, S., Zumbansen, M., Stoffel, W. J. Biol. Chem. (2000) [Pubmed]
  29. CD40 signals apoptosis through FAN-regulated activation of the sphingomyelin-ceramide pathway. Ségui, B., Andrieu-Abadie, N., Adam-Klages, S., Meilhac, O., Kreder, D., Garcia, V., Bruno, A.P., Jaffrézou, J.P., Salvayre, R., Krönke, M., Levade, T. J. Biol. Chem. (1999) [Pubmed]
  30. A TrkA-to-p75NTR molecular switch activates amyloid beta-peptide generation during aging. Costantini, C., Weindruch, R., Della Valle, G., Puglielli, L. Biochem. J. (2005) [Pubmed]
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