Affinage

SMPD2

Sphingomyelin phosphodiesterase 2 · UniProt O60906

Round 2 corrected
Length
423 aa
Mass
47.6 kDa
Annotated
2026-04-28
50 papers in source corpus 18 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMPD2 encodes a Mg²⁺-dependent neutral sphingomyelinase that hydrolyzes sphingomyelin to ceramide and phosphocholine, functioning as a stress-responsive ceramide generator that couples lipid signaling to cell cycle arrest, apoptosis, and mitochondrial homeostasis. Catalysis requires conserved residues E100, N233, H334, and a P-loop-like domain (D163, K168) involved in Mg²⁺ coordination, and the enzyme is activated by anionic phospholipids (phosphatidylserine, cardiolipin) binding to its second transmembrane domain and C-terminus (PMID:12820895, PMID:12244059). JNK-mediated phosphorylation at Ser-270 activates SMPD2 under diverse stresses (UV, oxidative stress, TNF-α, anti-Fas), and the resulting ceramide drives G0/G1 arrest through Rb hypophosphorylation and p21 induction, or apoptosis via JNK/p38 MAPK cascades (PMID:25168245, PMID:15051724, PMID:20836852). Studies of the yeast ortholog Isc1p further establish roles in mitochondrial ceramide generation critical for respiratory adaptation, mitochondrial morphology maintenance, and integration with checkpoint signaling through Swe1p stability and PP2A-Cdc55 (PMID:17880915, PMID:19158081, PMID:32205408).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1998 High

    Molecular cloning established SMPD2 as a ubiquitously expressed, Mg²⁺-dependent integral membrane neutral sphingomyelinase, resolving the molecular identity of a long-sought mammalian nSMase activity.

    Evidence Cloning and stable overexpression in U937 and HEK cells with in vitro SMase activity assays

    PMID:9520418

    Open questions at the time
    • Overexpression did not robustly activate JNK/NFκB, leaving signaling function uncertain
    • Endogenous loss-of-function data were lacking
  2. 1999 High

    A functional reassignment revealed that overexpressed SMPD2 acts primarily as a lyso-PAF phospholipase C in cellular contexts, raising questions about whether sphingomyelin is its physiological substrate in vivo.

    Evidence Metabolic labeling with [³H]palmitic acid and in vitro substrate specificity assays in overexpressing cells

    PMID:10608884

    Open questions at the time
    • Controversy about primary substrate identity not fully resolved for endogenous enzyme
    • Lyso-PAF PLC activity not tested in all relevant cell types
  3. 2000 High

    Identification of the yeast ortholog ISC1 as an inositol phosphosphingolipid phospholipase C that accounts for all neutral SMase activity in yeast provided genetic tractability and confirmed sphingolipid hydrolysis as the conserved core function.

    Evidence Gene deletion eliminating neutral SMase/IPS-PLC activity, metabolic labeling showing sphingolipid accumulation in isc1Δ

    PMID:11006294

    Open questions at the time
    • Yeast sphingolipid substrates differ from mammalian sphingomyelin
    • Whether mammalian SMPD2 performs equivalent in vivo sphingomyelin hydrolysis remained unclear
  4. 2002 High

    Structural dissection of ISC1 revealed that anionic phospholipid activation requires the second transmembrane domain and C-terminal positively charged residues, and that the N-terminal catalytic domain must be recruited to the membrane by PS for activity.

    Evidence Site-directed mutagenesis, lipid-protein overlay assays, reconstitution from separate enzyme fragments

    PMID:12244059

    Open questions at the time
    • No crystal structure to confirm membrane-recruitment model
    • Mammalian SMPD2 C-terminal domain not independently tested
  5. 2003 High

    Systematic active-site mutagenesis identified essential catalytic residues (E100, N233, H334) and a P-loop-like domain (D163, K168) required for Mg²⁺ coordination, defining the catalytic mechanism.

    Evidence Site-directed mutagenesis of ISC1 with full enzyme kinetics (Km, Vmax, Mg²⁺ Ka)

    PMID:12820895

    Open questions at the time
    • No structural data confirming Mg²⁺ coordination geometry
    • Applicability of all residue assignments to mammalian SMPD2 inferred by homology
  6. 2003 High

    Biochemical characterization of mouse nSMase2 confirmed it as a bona fide neutral sphingomyelinase that reduces cellular sphingomyelin, elevates ceramide, suppresses growth, and is activated by TNF-α, resolving the substrate identity debate for the mammalian enzyme.

    Evidence Expression in isc1Δ yeast, SM/ceramide mass measurements in MCF7 cells, TNF-α stimulation

    PMID:12566438

    Open questions at the time
    • Endogenous loss-of-function data for mammalian SMPD2 not yet available
    • Relative contribution of lyso-PAF PLC vs. SMase activity in vivo still unresolved
  7. 2004 High

    Endogenous SMPD2 was shown to function as a growth suppressor that generates C24 ceramide species at confluence, enforcing G0/G1 arrest via Rb hypophosphorylation and p21 induction, and redistributes to the plasma membrane upon cell–cell contact.

    Evidence siRNA knockdown in MCF7 cells with flow cytometry, ceramide species analysis, Rb/p21 western blotting, immunofluorescence

    PMID:15051724

    Open questions at the time
    • Mechanism of confluence-triggered SMPD2 upregulation unknown
    • Direct link between C24 ceramide species and Rb/p21 pathway not established
  8. 2007 High

    Isc1p was found to localize to the outer mitochondrial membrane during the post-diauxic phase, where it generates α-hydroxylated phytoceramide essential for mitochondrial function under stress, establishing a mitochondrial role for this enzyme family.

    Evidence Subcellular fractionation of purified mitochondria, LC/MS sphingolipidomics, respiratory competence and oxidative stress assays in isc1Δ

    PMID:17880915

    Open questions at the time
    • Whether mammalian SMPD2 also translocates to mitochondria is unknown
    • Mechanism of Isc1p mitochondrial targeting not defined
  9. 2009 High

    ISC1 was positioned as a regulator of the G2/M checkpoint through control of Swe1p stability and Cdc28-Tyr19 phosphorylation, and as necessary for metabolic gene reprogramming during the diauxic shift, broadening its role beyond lipid metabolism to cell cycle and metabolic adaptation.

    Evidence Double-mutant epistasis (isc1Δ/swe1Δ, Cdc28-Y19F), flow cytometry, microarray gene expression profiling

    PMID:19158081 PMID:19179331

    Open questions at the time
    • Signaling intermediates between ceramide and Swe1p stabilization not identified
    • Transcriptional regulation mechanism downstream of mitochondrial ceramide unclear
  10. 2010 High

    SMPD2 was validated as the central in vivo mediator of stress-induced ceramide generation and apoptosis, shown in cigarette smoke-exposed mouse lung (heterozygous KO) and in leukemia cells where it acts upstream of MKK4–JNK/p38 MAPK cascades.

    Evidence nSMase2 heterozygous mice, in vivo siRNA, aSMase KO controls, siRNA and GW4869 in leukemia cell lines with kinase phosphorylation readouts

    PMID:20448054 PMID:20836852

    Open questions at the time
    • Full knockout mouse phenotype not reported
    • Tissue-specific contributions of SMPD2 vs. SMPD3 not delineated
  11. 2014 High

    JNK-mediated phosphorylation at Ser-270 was identified as the activating post-translational modification of SMPD2, explaining how diverse stresses converge on ceramide generation and apoptosis.

    Evidence S270A/S270E mutagenesis, JNK inhibitor, RNAi in zebrafish and Jurkat cells, multiple stress stimuli

    PMID:25168245

    Open questions at the time
    • Structural basis for how S270 phosphorylation increases catalytic activity unknown
    • Other potential phosphorylation sites not systematically mapped
  12. 2020 Medium

    ISC1 was integrated into the spindle assembly checkpoint pathway, with SAC genes acting upstream and PP2A-Cdc55 acting as a ceramide-activated phosphatase downstream, linking sphingolipid signaling to mitotic fidelity.

    Evidence Synthetic lethality with SAC gene deletions, benomyl sensitivity, epistasis with CDC55

    PMID:32205408

    Open questions at the time
    • Direct biochemical activation of PP2A-Cdc55 by ceramide species not shown
    • Mammalian counterpart of this checkpoint connection not tested
  13. 2022 Medium

    A cross-inhibitory feedback loop between Isc1 and the phospholipase Pgc1 was discovered, integrating sphingolipid and phospholipid metabolism for mitochondrial homeostasis.

    Evidence Double-mutant rescue (pgc1Δ isc1Δ), in vitro enzyme inhibition assays, PE and cytochrome c oxidase measurements

    PMID:36377885

    Open questions at the time
    • Quantitative flux through this feedback loop in vivo not measured
    • Mammalian equivalent of Pgc1 counterpart not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SMPD2 catalysis and membrane association, the in vivo partitioning between SMase and lyso-PAF PLC activities, whether mammalian SMPD2 translocates to mitochondria, and the full phenotype of a complete SMPD2 knockout mouse.
  • No crystal or cryo-EM structure available
  • Complete SMPD2 knockout mouse not characterized
  • Relative physiological importance of lyso-PAF PLC vs. SMase activity unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-5357801 Programmed Cell Death 3
Partners
MAPK8MAPK9PP2A

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 The cloned murine and human SMPD2 (then called nSMase) was identified as a ubiquitously expressed integral membrane protein with Mg2+-dependent neutral sphingomyelinase activity at the plasma membrane. Stable overexpression in U937 and HEK cells confirmed sphingomyelinase activity, though TNF-α stimulation produced only modest ceramide elevation without activating JNK, NFκB, or ERK1 pathways in these overexpressor lines. Molecular cloning, stable overexpression, in vitro SMase activity assays, signal transduction assays (JNK, NFκB, PARP cleavage) Proceedings of the National Academy of Sciences of the United States of America High 9520418
1999 The originally cloned putative nSMase (SMPD2/nSMase1) was shown to function primarily as a lyso-platelet-activating factor phospholipase C (lyso-PAF-PLC) rather than as a sphingomyelinase in cells. Overexpression did not alter ceramide or sphingomyelin metabolism but caused accumulation of 1-O-alkyl-sn-glycerol, and in vitro assays demonstrated lyso-PAF and lyso-PC are substrates. Radiolabeling with [3H]palmitic acid/[3H]hexadecanol, in vitro substrate assays, immunoprecipitation of enzyme activity, metabolic labeling The Journal of biological chemistry High 10608884
2000 The yeast SMPD2 ortholog ISC1 (YER019w) was identified as an inositol phosphosphingolipid phospholipase C (IPS-PLC). Overexpression greatly increased neutral SMase activity in a phosphatidylserine-dependent manner; ISC1 deletion eliminated neutral SMase and IPS-PLC activities and caused accumulation of complex sphingolipids, establishing ISC1 as the first enzyme in complex sphingolipid catabolism in yeast. Overexpression, gene deletion, in vitro enzyme activity assays, [3H]dihydrosphingosine metabolic labeling The Journal of biological chemistry High 11006294
2002 Structural determinants for ISC1 activation by anionic phospholipids were defined. The second transmembrane domain (TMII) and C-terminus are required and sufficient for binding phosphatidylserine (PS), cardiolipin (CL), and phosphatidylglycerol (PG). Positively charged residues at the C-terminus mediate PS/CL/PG interaction and enzyme activation. Reconstitution experiments showed that the N-terminal catalytic domain and C-terminal region must interact for enzymatic activity, suggesting PS pulls the catalytic domain to the membrane. Site-directed mutagenesis, deletion mutants, lipid-protein overlay assays, GFP fusion heterologous expression, enzymatic reconstitution from separate fragments The Journal of biological chemistry High 12244059
2002 ISC1-encoded inositol phosphosphingolipid phospholipase C is involved in Na+/Li+ halotolerance in yeast. Deletion of ISC1 severely impaired growth on NaCl/LiCl, reduced Na+/Li+-stimulated ENA1 (cation-extrusion ATPase) expression, and decreased Ena1p-dependent ion extrusion, placing ISC1-dependent sphingolipid hydrolysis as an early event in salt-induced ENA1 signaling. Gene deletion, growth assays, ENA1-lacZ reporter assays, ion extrusion measurements European journal of biochemistry Medium 12180980
2003 Catalytic residues of ISC1 were defined by site-directed mutagenesis: E100, N233, and H334 are essential for catalysis. A P-loop-like domain (G162–S169) was identified; D163A and K168A completely abolished activity, while G162A, G167A, and S169A reduced Vmax without affecting Km. The P-loop-like domain is involved in Mg2+ binding and optimal catalytic efficiency, potentially interacting with the PS activator. Site-directed mutagenesis, in vitro enzyme kinetics (Km, Vmax, Mg2+ Ka), phosphatidylserine binding assays Biochemistry High 12820895
2003 Mouse nSMase2 (SMPD2) was biochemically characterized as a bona fide neutral sphingomyelinase. The enzyme requires Mg2+, is activated by phosphatidylserine, and is inhibited by GW4869. Overexpression in MCF7 cells decreased sphingomyelin levels by 40% and increased ceramide by 60%. nSMase2 overexpression reduced cell growth by 30–40%, and TNF-α induced ~50% activation of nSMase2 in overexpressing MCF7 cells. Heterologous expression in isc1Δ yeast, in vitro activity assays, SM/ceramide mass measurement in MCF7 cells, [3H] labeling, cell growth assays, TNF-α stimulation The Journal of biological chemistry High 12566438
2004 Endogenous nSMase2 (SMPD2) functions as a growth suppressor in MCF7 cells. At confluence, nSMase2 mRNA was upregulated ~5-fold, neutral SMase activity increased 119%, and ceramide (particularly very long chain C24:1 and C24:0 species) was elevated. siRNA knockdown of nSMase2 increased S-phase cells by 59%, prevented hypophosphorylation of retinoblastoma protein, and blocked p21(WAF1) induction. nSMase2 also redistributed from cytoplasm to plasma membrane upon confluence. siRNA knockdown, cell cycle analysis (flow cytometry), ceramide mass measurement, western blotting (Rb phosphorylation, p21), immunofluorescence localization The Journal of biological chemistry High 15051724
2004 Expression of FLAG-tagged mouse nSMase2 (SMPD2) in primary rat hepatocytes via adenoviral gene transfer increased cellular ceramide levels and potentiated IL-1β-induced JNK phosphorylation 1.5–2-fold. This potentiation was mediated by a PP2A family phosphatase, possibly by modulating IRAK phosphorylation. nSMase2 localized to the plasma membrane in HepG2 cells. Adenovirus-mediated gene transfer, in vitro SMase activity assay, ceramide measurement, JNK phosphorylation assay, phosphatase inhibitor studies, immunofluorescence FASEB journal Medium 15059969
2007 Yeast Isc1p (SMPD2 ortholog) localizes to the outer mitochondrial membrane as an integral membrane protein in the post-diauxic phase. Endogenous Isc1p activity was enriched in highly purified mitochondria. Mitochondria from isc1Δ cells showed 93% loss of alpha-hydroxylated phytoceramide. Functionally, isc1Δ exhibited higher respiratory-deficient cell rates at high temperature and sensitivity to hydrogen peroxide, establishing mitochondrial ceramide generation by Isc1p as important for mitochondrial function. Subcellular fractionation, western blotting of mitochondrial fractions, LC/MS sphingolipid profiling, respiratory competence assays, oxidative stress sensitivity assays Biochimica et biophysica acta High 17880915
2009 ISC1 (SMPD2 ortholog) regulates the G2/M checkpoint in yeast. isc1Δ cells treated with hydroxyurea (HU) showed G2/M block associated with elevated Cdc28-Tyr19 phosphorylation. Sustained Swe1p (the kinase phosphorylating Cdc28-Tyr19) levels in isc1Δ cells after HU were responsible; deletion of SWE1 in isc1Δ overcame the G2/M block. A Cdc28-Y19F mutant also rescued isc1Δ from G2/M arrest, placing Isc1p as an upstream regulator of Swe1p stability. Flow cytometry cell cycle analysis, western blotting (Cdc28-pTyr19, Swe1p), double-mutant genetic epistasis (isc1Δ/swe1Δ, isc1Δ/cdc28-Y19F), HU sensitivity assays The Journal of biological chemistry High 19158081
2009 Isc1p (SMPD2 ortholog) in yeast mitochondria is required for metabolic adaptation during the diauxic shift. isc1Δ cells showed defective aerobic respiration despite intact intrinsic mitochondrial functions (normal mtDNA, O2 consumption, membrane potential). Microarray analysis revealed failure to upregulate genes for nonfermentable carbon metabolism. The mitochondrial requirement for this nuclear gene induction overlapped with Adr1p-, Snf1p-, and Cat8p-dependent genes, but did not activate the retrograde response. Microarray gene expression, respiratory assays, mitochondrial membrane potential measurement, mtDNA analysis, genetic analysis with petite cells The Journal of biological chemistry Medium 19179331
2010 nSMase2 (SMPD2) was identified as a critical mediator of Withanolide D-induced apoptosis in leukemia cells. siRNA knockdown of nSMase2 and the nSMase inhibitor GW4869 significantly reduced ceramide generation, MKK4 and MKK3/6 phosphorylation, and apoptosis in K562 and MOLT-4 cells, placing SMPD2 upstream of the JNK/p38 MAPK cascade in this apoptotic pathway. siRNA knockdown of nSMase2, pharmacological inhibition (GW4869), ceramide measurement, kinase phosphorylation assays (JNK, p38, MKK4, MKK3/6), apoptosis assays Molecular cancer Medium 20836852
2010 nSMase2 (SMPD2) was established as the central in vivo mediator of cigarette smoke-induced ceramide generation and apoptosis in lung. Heterozygous nSMase2 mice showed significantly decreased ceramide after CS exposure; aSMase knockout mice maintained wild-type ceramide levels. Anti-nSMase2 siRNA abrogated CS-induced ceramide elevation and TUNEL-positive cells. N-acetyl cysteine treatment also abrogated these effects, linking oxidative stress to nSMase2 activation. nSMase2 heterozygous mouse model, aSMase knockout mice, in vivo siRNA, ceramide measurement in lung tissue, TUNEL assay, N-acetyl cysteine treatment American journal of respiratory cell and molecular biology High 20448054
2011 ISC1 (SMPD2 ortholog) interacts with the DNA integrity checkpoint pathway to control cell morphology. isc1Δ cells under HU treatment exhibited morphological aberrations, cell-wall defects, and defects in actin depolymerization. Genetic analysis showed synthetic interactions: isc1Δ combined with mrc1Δ, tof1Δ, or csm3Δ enhanced morphological defects, while isc1Δ/rad9Δ reduced them. Swe1 and Cdk1 were identified as key mediators, and Rad53 dosage partially influenced isc1Δ morphology. Genetic epistasis (double mutants), flow cytometry, morphological analysis, actin staining, checkpoint gene deletions Genetics Medium 21840863
2014 SMPD2 (nSMase1 in zebrafish nomenclature) is phosphorylated by JNK at Ser-270, which activates the enzyme to generate ceramide and induce apoptosis. S270A substitution blocked phosphorylation and activation; S270E (phosphomimetic) mimicked activation. JNK inhibitor SP600125 blocked nSMase1 phosphorylation and ceramide generation. Multiple stresses (heat shock, UV, H2O2, anti-Fas) induced this phosphorylation. MAPK8/9 or SMPD2 RNAi knockdown in human Jurkat T cells decreased ceramide and stress/cytokine-induced apoptosis. Site-directed mutagenesis (S270A, S270E), JNK inhibitor treatment, RNAi knockdown in zebrafish and human Jurkat cells, ceramide measurement, apoptosis assays, phosphorylation assays Cell death and differentiation High 25168245
2020 In yeast, ISC1 (SMPD2 ortholog) is positioned within the spindle assembly checkpoint (SAC) pathway. Deletion of SAC genes (BUB1, MAD1, BIM1, KAR3) phenocopied ISC1 deletion, and spindle checkpoint genes act upstream of Isc1. ISC1 deletion mutants were sensitive to benomyl (SAC defect indicator) and failed spindle elongation in HU-treated cells (similar to bub1Δ). PP2A-Cdc55 ceramide-activated phosphatase acts downstream of Isc1p, coupling the spindle checkpoint to CDC55-mediated nuclear functions. Synthetic lethality analysis, gene deletion, benomyl sensitivity assays, spindle elongation imaging, epistasis with cdc55, concordance analysis Molecular and cellular biology Medium 32205408
2022 In yeast, Isc1 (SMPD2 ortholog) and the PG-specific phospholipase Pgc1 functionally cooperate to regulate mitochondrial function. Deletion of PGC1 rescued the mitochondrial dysfunction (reduced PE levels and cytochrome c oxidase activity) in isc1Δ cells. The Pgc1 substrate PG inhibited Isc1 activity in vitro. Products of Isc1-mediated hydrolysis partially inhibited Pgc1 activity, establishing a cross-inhibitory feedback loop linking sphingolipid and phospholipid metabolism for mitochondrial homeostasis. Double-mutant genetic rescue (pgc1Δ isc1Δ), in vitro enzyme activity assays with PG substrate/inhibitor, PE and cytochrome c oxidase activity measurements Microbiology spectrum Medium 36377885
2025 Overexpression of Isc1 (SMPD2 ortholog) in chronologically aged yeast prevented dramatic mitochondrial morphological changes (large rounded morphology, decreased outer membrane/matrix co-localization, decreased membrane potential) that normally occur during aging. Similar sphingolipid-dependent mitochondrial morphological transitions were observed following acute oxidative stress, suggesting SMPD2-ortholog activity promotes adaptive mitochondrial remodeling. Isc1 overexpression, confocal microscopy of mitochondrial morphology, pharmacological and genetic perturbation of sphingolipid biosynthesis, mitochondrial membrane potential measurements bioRxivpreprint Low

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Trk receptors: roles in neuronal signal transduction. Annual review of biochemistry 2042 12676795
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Many sequence variants affecting diversity of adult human height. Nature genetics 520 18391951
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2004 Ceramide synthesis and metabolism as a target for cancer therapy. Cancer letters 265 15013522
1998 Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling? Proceedings of the National Academy of Sciences of the United States of America 251 9520418
2004 Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis. The Journal of investigative dermatology 236 15175033
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2003 Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism. The Journal of biological chemistry 170 12566438
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2007 Metabolism and biological functions of two phosphorylated sphingolipids, sphingosine 1-phosphate and ceramide 1-phosphate. Progress in lipid research 140 17449104
2004 Role for mammalian neutral sphingomyelinase 2 in confluence-induced growth arrest of MCF7 cells. The Journal of biological chemistry 139 15051724
2000 Identification of ISC1 (YER019w) as inositol phosphosphingolipid phospholipase C in Saccharomyces cerevisiae. The Journal of biological chemistry 134 11006294
2010 Identification and characterization of murine mitochondria-associated neutral sphingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5. The Journal of biological chemistry 109 20378533
2014 Stress-induced ceramide generation and apoptosis via the phosphorylation and activation of nSMase1 by JNK signaling. Cell death and differentiation 98 25168245
2007 Oxidative stress kills human primary oligodendrocytes via neutral sphingomyelinase: implications for multiple sclerosis. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 94 18040843
2004 Human immunodeficiency virus type 1 gp120 induces apoptosis in human primary neurons through redox-regulated activation of neutral sphingomyelinase. The Journal of neuroscience : the official journal of the Society for Neuroscience 92 15509740
1999 Function of the cloned putative neutral sphingomyelinase as lyso-platelet activating factor-phospholipase C. The Journal of biological chemistry 91 10608884
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2014 Human-chromatin-related protein interactions identify a demethylase complex required for chromosome segregation. Cell reports 80 24981860
2020 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. Cell reports 79 32814053
2004 Expression of neutral sphingomyelinase-2 (NSMase-2) in primary rat hepatocytes modulates IL-beta-induced JNK activation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 75 15059969
2010 Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Molecular cancer 74 20836852
2007 Isc1 regulates sphingolipid metabolism in yeast mitochondria. Biochimica et biophysica acta 73 17880915
2010 Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury. American journal of respiratory cell and molecular biology 69 20448054
2013 Ceramide mediates Ox-LDL-induced human vascular smooth muscle cell calcification via p38 mitogen-activated protein kinase signaling. PloS one 64 24358176
2009 ISC1-dependent metabolic adaptation reveals an indispensable role for mitochondria in induction of nuclear genes during the diauxic shift in Saccharomyces cerevisiae. The Journal of biological chemistry 48 19179331
2008 Thematic review series: sphingolipids. ISC1 (inositol phosphosphingolipid-phospholipase C), the yeast homologue of neutral sphingomyelinases. Journal of lipid research 35 18305313
2006 Lactosylceramide is required in apoptosis induced by N-Smase. Glycoconjugate journal 35 16691498
2014 Critical determinants of mitochondria-associated neutral sphingomyelinase (MA-nSMase) for mitochondrial localization. Biochimica et biophysica acta 28 25484313
2002 Structural requirements for selective binding of ISC1 to anionic phospholipids. The Journal of biological chemistry 28 12244059
2011 Characterization of inositol phospho-sphingolipid-phospholipase C 1 (Isc1) in Cryptococcus neoformans reveals unique biochemical features. FEBS letters 27 21256847
2018 Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent. Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 26 29679745
2003 Functional analysis of ISC1 by site-directed mutagenesis. Biochemistry 25 12820895
2002 ISC1-encoded inositol phosphosphingolipid phospholipase C is involved in Na+/Li+ halotolerance of Saccharomyces cerevisiae. European journal of biochemistry 25 12180980
2009 Hydroxyurea sensitivity reveals a role for ISC1 in the regulation of G2/M. The Journal of biological chemistry 21 19158081
2011 Cellular morphogenesis under stress is influenced by the sphingolipid pathway gene ISC1 and DNA integrity checkpoint genes in Saccharomyces cerevisiae. Genetics 19 21840863
2023 Chronic nSMase inhibition suppresses neuronal exosome spreading and sex-specifically attenuates amyloid pathology in APP knock-in Alzheimer's disease mice. Neurobiology of disease 17 37364689
2022 Two Different Phospholipases C, Isc1 and Pgc1, Cooperate To Regulate Mitochondrial Function. Microbiology spectrum 7 36377885
2020 Yeast Sphingolipid Phospholipase Gene ISC1 Regulates the Spindle Checkpoint by a CDC55-Dependent Mechanism. Molecular and cellular biology 6 32205408
2014 Differential modulation of S1PR(1-5) and specific activities of SphK and nSMase in pulmonary and cerebral tissues of rats exposed to hypobaric hypoxia. Lipids 4 25398597
2026 In differentiated HL-60 neutrophil-like cells, MRP1- (ABCC1-) mediated glutathione efflux stimulated by BzATP and P2X7 receptor signalling regulates exosome release through nSMase activity. Biochemical and biophysical research communications 0 41856059