Disease relevance of Smpd2

• The rat nSMase expressed in Escherichia coli catalyzed sphingomyelin hydrolysis at neutral pH in a Mg(2+)-dependent manner, and required Triton X-100, dithiothreitol, and KCl for its full activity [1].
• We report here that acute exposure of WEHI-231 cells (murine B-cell lymphoma) to OE activates neutral sphingomyelinase, induces ceramide production and increases intracellular reactive oxygen species [2].
• Omega-3 polyunsaturated fatty acids attenuate breast cancer growth through activation of a neutral sphingomyelinase-mediated pathway [3].
• Treatment of the tumour cells with neutral sphingomyelinase drastically reduced the amount of wild-type p53 fibrosarcoma cell proliferation over 72 h in a clear dose-response (0.2-1.0 U ml(-1) nSMase) [4].
• Generation of proapoptotic sphingolipids by neutral sphingomyelinase activation is an early response to hypoxia/reoxygenation (HR) in cardiomyocytes [5].

High impact information on Smpd2

• Ceramide generated by N-SMase directs the activation of proline-directed serine/threonine protein kinase(s) and phospholipase A2 [6].
• Although the C-terminal region is believed to be responsible for apoptosis induction, the functions of more membrane-proximal domains, including the domain that couples to neutral sphingomyelinase activation, are not yet fully elucidated [7].
• The WD-40 repeat protein FAN binds to a distinct domain of the p55 receptor for tumor necrosis factor (TNF) and signals the activation of neutral sphingomyelinase (N-SMase) [8].
• An essential role of FAN in the TNF-induced activation of N-SMase was demonstrated using thymocytes from FAN knockout mice [8].
• The cloned nSMase will facilitate further controlled experiments aiming at the definition of a possible role of ceramide as signal transduction molecule [9].

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

• Acid and neutral sphingomyelinase, ceramide synthase, and acid ceramidase activities in cutaneous aging [17].
• The unaltered metabolism of lysophosphatidylcholine or lyso-platelet-activating factor excludes the proposed role of nSMase 1 as a lysophospholipase C [12].
• Cloning and expression of rat neutral sphingomyelinase: enzymological characterization and identification of essential histidine residues [1].
• (d) The activity of neutral sphingomyelinase increased after addition of RA, maintained high levels in RA-differentiated cells, and returned to the initial levels with removal of RA [18].
• Previous results have indicated that the generation of ceramide by hydrolysis of sphingomyelin by magnesium-dependent neutral sphingomyelinase 1 (NSM1) is reversibly inhibited by hydrogen peroxide (H2O2) and oxidized glutathione (GSSG) [19].

Regulatory relationships of Smpd2

• We have previously shown that a cytoplasmic region of TNF-R55 distinct from the death domain regulates the activation of N-SMase through binding of the adapter protein FAN [20].
• Myelin contains neutral sphingomyelinase activity that is stimulated by tumor necrosis factor-alpha [21].
• The CD40-ligand stimulates T-lymphocytes via the neutral sphingomyelinase: a novel function of the CD40-ligand as signalling molecule [22].

Other interactions of Smpd2

• The N-SMase activation domain is distinct from the death domain and incapable of induction of A-SMase, NF-kappaB, and cytotoxicity [23].
• We also addressed the recent proposal that nSMase 1 possesses lysophospholipase C activity [12].
• Because caspase-8 and factor associated with neutral sphingomyelinase activation (FAN) have been implicated as proximal mediators of TNF-alpha-associated apoptosis, their role in lysosomal permeabilization was examined [24].
• P75NTR signaling independent of TrkA, such as increased neutral sphingomyelinase (NSMase) activity causing enhanced levels of ceramide, were not detected after exposure of hippocampal neurons to NGF [25].
• Evidence that neutral sphingomyelinase of cultured murine neuroblastoma cells is oriented externally on the plasma membrane [26].

Analytical, diagnostic and therapeutic context of Smpd2

• To elucidate the function of the first cloned Mg(2+)-dependent, neutral sphingomyelinase (nSMase 1) in sphingomyelin catabolism and its potential role in signaling processes in a genetic and molecular approach, we have generated an nSMase 1-null mutant mouse line by gene targeting [12].
• 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 [27].
• Cell fractionation combined with immunoprecipitation studies localized the nSMase1 protein predominantly in the microsomal fraction [28].
• Altogether, these results strongly suggest that CD40 ligation can activate via FAN a neutral sphingomyelinase-mediated ceramide pathway that is involved in the cell growth inhibitory effects of CD40 [29].
• In contrast with caloric restriction, which prevents the age-associated up-regulation of p75NTR expression, nSMase inhibitors block the activation of ceramide [30].

References