{"gene":"SGMS1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2007,"finding":"SMS1 localizes to the Golgi and SMS2 localizes to the plasma membrane in HeLa cells; both function as the key SM synthases at these respective compartments. RNAi-mediated depletion of either SMS1 or SMS2 caused substantial decreases in sphingomyelin production, accumulation of ceramide, and a block in cell growth. External addition of SM did not restore growth, indicating the biological role of SMS synthases extends beyond SM formation.","method":"RNA interference (RNAi) knockdown, lipid analysis, subcellular fractionation/localization, cell growth assays in HeLa cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional data with two orthogonal methods (RNAi + lipid mass measurements + growth assays), replicated across two isoforms with clear compartmental distinction","pmids":["17449912"],"is_preprint":false},{"year":2008,"finding":"SMS1 knockdown in Jurkat T cells (SMS1-siRNA) severely reduced membrane sphingomyelin expression and impaired TCR signal transduction: CD3 stimulation failed to induce CD69 expression, cell adhesion, proliferation, and TCR clustering. CD3-induced tyrosine phosphorylation, LAT association with ZAP-70 and Grb2, and PKC phosphorylation were impaired. Translocation of TCR, ZAP-70, and PKC into lipid rafts was markedly decreased, indicating SMS1-produced sphingomyelin is essential for lipid raft integrity and TCR signaling.","method":"siRNA knockdown of SMS1 in Jurkat T cells, flow cytometry, immunoprecipitation, lipid raft fractionation, proliferation assays","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with multiple orthogonal readouts (lipid raft fractionation, signaling molecule phosphorylation, functional T cell activation assays), single lab","pmids":["18820264"],"is_preprint":false},{"year":2005,"finding":"The mouse SMS1 gene is alternatively spliced to produce four mRNA transcripts (SMS1alpha1, SMS1alpha2, SMS1beta, SMS1gamma) encoding three different proteins (SMS1alpha, SMS1beta, SMS1gamma). SMS1alpha prevents Bax-induced growth inhibition in a yeast-based assay, while SMS1beta neither prevents nor enhances the effects of Bax or SMS1alpha, indicating isoform-specific functional differences. SMS1 transcripts increase in response to pro-apoptotic TNF-alpha.","method":"RT-PCR, genomic structure analysis, yeast functional complementation assay (Bax growth inhibition), Northern blot","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast functional assay with isoform comparison, multiple transcript characterization by RT-PCR, single lab with two orthogonal approaches","pmids":["16226406"],"is_preprint":false},{"year":2021,"finding":"ROR2 depletion in dental pulp stem cells (DPSCs) inhibits SMS1 expression and sphingomyelin biosynthesis. Mechanistically, ROR2 inhibits STK4 phosphorylation, which promotes FOXO1 nuclear translocation; nuclear FOXO1 directly binds the SMS1 promoter and represses its transcription. STK4 inhibition or FOXO1 knockdown upregulated SMS1 expression and increased SM levels, reversing the senescence phenotype. This defines a ROR2/STK4-FOXO1/SMS1 regulatory axis controlling sphingomyelin synthesis and DPSC senescence.","method":"siRNA knockdown, overexpression, ChIP (FOXO1 binding to SMS1 promoter), Western blot for phosphorylation, proliferation assays, lipid analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct FOXO1 binding to SMS1 promoter, supported by genetic epistasis (KD of pathway components), single lab","pmids":["34278704"],"is_preprint":false},{"year":2024,"finding":"SGMS1 promotes osteogenic differentiation of mesenchymal stem cells (MSCs) by regulating ceramide/sphingomyelin metabolism: SGMS1 overexpression inhibits ceramide and increases sphingomyelin levels, thereby restraining PP2A activity and enhancing phosphorylated Akt, Runx2, and VEGF levels. SM treatment neutralized the suppressive effect of SGMS1 silencing on osteogenesis. SGMS1 transcription is regulated by Runx2 (feedback loop). SGMS1 promotes MSC-mediated angiogenesis via VEGF upregulation and accelerates bone regeneration in vivo.","method":"siRNA knockdown and overexpression of SGMS1, lipid measurements (ceramide/SM), Western blot (PP2A activity, pAkt, Runx2, VEGF), SM supplementation rescue experiments, in vivo rat bone regeneration model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (lipid analysis, signaling Western blots, rescue with SM, in vivo model), single lab","pmids":["38544565"],"is_preprint":false},{"year":2024,"finding":"Complete knockout of Sgms1 (exon 7 deletion, Sgms1tm1b) in mice causes progressive hearing loss with a consistently reduced endocochlear potential (~80 mV vs ~120 mV in controls). The stria vascularis showed irregular marginal cell surfaces and patchy loss of Kcnq1 expression, with marginal cells identified as the likely initial site of dysfunction. A partial knockdown allele (20% residual transcript) was sufficient for normal hearing, indicating a threshold requirement for SMS1 in maintaining endocochlear potential.","method":"Conditional/constitutive mouse knockout (Sgms1tm1b), auditory brainstem response, endocochlear potential measurement, immunofluorescence (Kcnq1), gene expression analysis of lateral wall","journal":"Hearing research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined molecular phenotype (endocochlear potential reduction), cellular localization of dysfunction (marginal cells, Kcnq1 loss), dose-response with partial knockdown allele, multiple physiological and molecular readouts","pmids":["39067415"],"is_preprint":false}],"current_model":"SGMS1 (sphingomyelin synthase 1) is a Golgi-localized enzyme that catalyzes the transfer of phosphocholine from phosphatidylcholine to ceramide, producing sphingomyelin and diacylglycerol; its activity is required for sphingomyelin homeostasis in cellular membranes, lipid raft integrity necessary for TCR signaling, osteogenic differentiation of MSCs via a ceramide/PP2A/Akt pathway, and maintenance of the endocochlear potential in the inner ear stria vascularis marginal cells, with its transcription regulated by a ROR2/STK4-FOXO1 axis and by Runx2."},"narrative":{"mechanistic_narrative":"SGMS1 (sphingomyelin synthase 1) is a Golgi-localized enzyme that governs cellular sphingomyelin homeostasis, partitioning the ceramide/sphingomyelin balance that underlies membrane organization and downstream signaling [PMID:17449912]. Depletion of SMS1 lowers sphingomyelin and causes ceramide accumulation, blocking cell growth in a manner not rescued by exogenous sphingomyelin, indicating its role extends beyond bulk lipid supply [PMID:17449912]. By supplying sphingomyelin to membrane microdomains, SMS1 is required for lipid raft integrity: its loss in T cells prevents translocation of TCR, ZAP-70, and PKC into rafts and impairs CD3-induced signaling and T cell activation [PMID:18820264]. The same ceramide/sphingomyelin switch links SMS1 to differentiation programs—in mesenchymal stem cells SGMS1 lowers ceramide and restrains PP2A, enhancing phosphorylated Akt, Runx2, and VEGF to drive osteogenesis and angiogenesis, with Runx2 feeding back onto SGMS1 transcription [PMID:38544565], while a ROR2/STK4–FOXO1 axis represses SGMS1 transcription through direct FOXO1 binding to its promoter [PMID:34278704]. At the organ level, SGMS1 is required to maintain the endocochlear potential, where its knockout in mice produces progressive hearing loss with stria vascularis marginal cell dysfunction and patchy Kcnq1 loss, and a threshold of residual expression suffices for normal hearing [PMID:39067415].","teleology":[{"year":2005,"claim":"Established the gene architecture of SMS1 and that its isoforms carry distinct functional outputs, opening the question of isoform-specific roles in cell survival.","evidence":"RT-PCR, genomic structure analysis, and yeast Bax-complementation assays of mouse SMS1 splice variants","pmids":["16226406"],"confidence":"Medium","gaps":["Functional readout limited to a yeast Bax-growth assay rather than mammalian cells","Mechanism by which SMS1alpha prevents Bax-induced growth inhibition not defined","Link between TNF-alpha induction and enzymatic activity not established"]},{"year":2007,"claim":"Defined SMS1 as the Golgi-resident sphingomyelin synthase whose activity is rate-limiting for SM production and cell growth, resolving where in the cell SM is made.","evidence":"RNAi knockdown with lipid mass measurements, subcellular localization, and growth assays in HeLa cells","pmids":["17449912"],"confidence":"High","gaps":["Mechanism linking ceramide accumulation to growth arrest not resolved","Catalytic mechanism and substrate kinetics not characterized in this study"]},{"year":2008,"claim":"Showed that SMS1-derived sphingomyelin is required for lipid raft integrity and TCR signal transduction, connecting the enzyme to immune cell activation.","evidence":"siRNA knockdown in Jurkat T cells with lipid raft fractionation, immunoprecipitation, and T cell activation assays","pmids":["18820264"],"confidence":"High","gaps":["Single cell line and single lab","Whether the defect reflects raft composition versus a specific SM-protein interaction not distinguished"]},{"year":2021,"claim":"Identified transcriptional control of SGMS1 by a ROR2/STK4–FOXO1 axis, explaining how SM synthesis is downregulated during stem cell senescence.","evidence":"siRNA/overexpression, ChIP for FOXO1 binding to the SMS1 promoter, and phosphorylation Westerns in dental pulp stem cells","pmids":["34278704"],"confidence":"Medium","gaps":["Single lab and single cell type","Direct FOXO1 binding site sequence not mapped beyond ChIP","Generality across other SGMS1-expressing tissues unknown"]},{"year":2024,"claim":"Placed SGMS1 within an osteogenic signaling circuit, showing it acts through the ceramide/PP2A/Akt–Runx2 pathway and forms a transcriptional feedback loop with Runx2.","evidence":"Knockdown/overexpression with lipid measurements, signaling Westerns, SM-supplementation rescue, and an in vivo rat bone regeneration model","pmids":["38544565"],"confidence":"Medium","gaps":["Direct enzymatic versus signaling contributions to PP2A restraint not separated","Single lab","Whether Runx2 binds the SGMS1 promoter directly not shown"]},{"year":2024,"claim":"Demonstrated an essential, dose-dependent in vivo role for SGMS1 in maintaining the endocochlear potential, localizing its physiological requirement to stria vascularis marginal cells.","evidence":"Constitutive Sgms1 knockout mice with auditory brainstem response, endocochlear potential measurement, and Kcnq1 immunofluorescence","pmids":["39067415"],"confidence":"High","gaps":["Molecular link between SM synthesis and Kcnq1 maintenance not defined","Whether the defect is cell-autonomous to marginal cells not established","Human hearing-loss association not tested in this study"]},{"year":null,"claim":"How SGMS1's local ceramide/sphingomyelin switch is mechanistically transduced into distinct downstream outputs—raft-dependent signaling, PP2A/Akt control, and ion-channel maintenance—across different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the enzyme in the corpus","Substrate channeling and compartment-specific lipid pools not dissected","Causal chain from SM levels to specific effector proteins (KCNQ1, PP2A) not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86VZ5","full_name":"Phosphatidylcholine:ceramide cholinephosphotransferase 1","aliases":["Medulla oblongata-derived protein","Protein Mob","Sphingomyelin synthase 1","Transmembrane protein 23"],"length_aa":413,"mass_kda":48.6,"function":"Major sphingomyelin synthase at the Golgi apparatus (PubMed:14685263, PubMed:17449912). Catalyzes the reversible transfer of phosphocholine moiety in sphingomyelin biosynthesis: in the forward reaction transfers phosphocholine head group of phosphatidylcholine (PC) on to ceramide (CER) to form ceramide phosphocholine (sphingomyelin, SM) and diacylglycerol (DAG) as by-product, and in the reverse reaction transfers phosphocholine from SM to DAG to form PC and CER. The direction of the reaction depends on the levels of CER and DAG in Golgi membranes (PubMed:14685263, PubMed:14976195, PubMed:17449912, PubMed:17982138, PubMed:19454763). Converts the newly synthesized CER, that is transported from the endoplasmic reticulum to the trans-Golgi by the Cer transport protein (CERT), to SM (PubMed:30242129). Can form a heteromeric complex with glucosylceramide synthase (GCS) increasing SMS activity and reducing glucosylceramide synthesis, a critical mechanism that controls the metabolic fate of CER in the Golgi (PubMed:30242129). Does not use free phosphorylcholine or CDP-choline as donor (PubMed:14685263, PubMed:14976195). Can also transfer phosphoethanolamine head group of phosphatidylethanolamine (PE) on to CER to form ceramide phosphoethanolamine (CPE) (By similarity). Regulates receptor-mediated signal transduction via mitogenic DAG and proapoptotic CER, as well as via SM, a structural component of membrane rafts that serve as platforms for signal transduction and protein sorting (PubMed:14976195, PubMed:17449912, PubMed:17982138). Plays a role in secretory transport via regulation of DAG pool at the Golgi apparatus and its downstream effects on PRKD1 (PubMed:18370930, PubMed:21980337)","subcellular_location":"Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q86VZ5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SGMS1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SGMS1","total_profiled":1310},"omim":[{"mim_id":"611573","title":"SPHINGOMYELIN SYNTHASE 1; SGMS1","url":"https://www.omim.org/entry/611573"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SGMS1"},"hgnc":{"alias_symbol":["MOB","MGC17342","SMS1"],"prev_symbol":["TMEM23"]},"alphafold":{"accession":"Q86VZ5","domains":[{"cath_id":"1.10.150.50","chopping":"3-76","consensus_level":"high","plddt":82.4914,"start":3,"end":76},{"cath_id":"-","chopping":"131-378","consensus_level":"high","plddt":88.9306,"start":131,"end":378}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VZ5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VZ5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86VZ5-F1-predicted_aligned_error_v6.png","plddt_mean":79.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SGMS1","jax_strain_url":"https://www.jax.org/strain/search?query=SGMS1"},"sequence":{"accession":"Q86VZ5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86VZ5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86VZ5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86VZ5"}},"corpus_meta":[{"pmid":"15766530","id":"PMC_15766530","title":"Control 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bacteria.","date":"2004","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/15212888","citation_count":20,"is_preprint":false},{"pmid":"16240174","id":"PMC_16240174","title":"Alfalfa Mob 1-like genes are expressed in reproductive organs during meiosis and gametogenesis.","date":"2005","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16240174","citation_count":20,"is_preprint":false},{"pmid":"19468312","id":"PMC_19468312","title":"Characterization and evolution of the cell cycle-associated mob domain-containing proteins in eukaryotes.","date":"2007","source":"Evolutionary bioinformatics online","url":"https://pubmed.ncbi.nlm.nih.gov/19468312","citation_count":19,"is_preprint":false},{"pmid":"11125315","id":"PMC_11125315","title":"Expression and regulation of the CXC-chemokines, GRO/KC and IP-10/mob-1 in rat seminiferous tubules.","date":"2000","source":"European cytokine 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Vibrio phage φpp2 with unique arrangements of the mob-like genes.","date":"2012","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22676552","citation_count":17,"is_preprint":false},{"pmid":"8572251","id":"PMC_8572251","title":"Mob-1 expression in IL-2-induced ARDS: regulation by TNF-alpha.","date":"1995","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/8572251","citation_count":17,"is_preprint":false},{"pmid":"21549185","id":"PMC_21549185","title":"Human sphingomyelin synthase 1 gene (SMS1): organization, multiple mRNA splice variants and expression in adult tissues.","date":"2011","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/21549185","citation_count":15,"is_preprint":false},{"pmid":"23063490","id":"PMC_23063490","title":"A sensitive cell-based method to screen for selective inhibitors of SMS1 or SMS2 using HPLC and a fluorescent substrate.","date":"2012","source":"Chemistry and physics of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/23063490","citation_count":15,"is_preprint":false},{"pmid":"15315829","id":"PMC_15315829","title":"Human gene MOB: structure specification and aspects of transcriptional activity.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/15315829","citation_count":15,"is_preprint":false},{"pmid":"7999801","id":"PMC_7999801","title":"The SMS1 gene encoding a serine-rich transmembrane protein suppresses the temperature sensitivity of the htr1 disruptant in Saccharomyces cerevisiae.","date":"1995","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/7999801","citation_count":15,"is_preprint":false},{"pmid":"9288136","id":"PMC_9288136","title":"The novel chemokine mob-1: involvement in adult respiratory distress syndrome.","date":"1997","source":"Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/9288136","citation_count":15,"is_preprint":false},{"pmid":"18552281","id":"PMC_18552281","title":"Characterization of KlGRR1 and SMS1 genes, two new elements of the glucose signaling pathway of Kluyveromyces lactis.","date":"2008","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/18552281","citation_count":14,"is_preprint":false},{"pmid":"2169281","id":"PMC_2169281","title":"Mobilization of Escherichia coli R1 silver-resistance plasmid pJT1 by Tn5-Mob into Escherichia coli C600.","date":"1990","source":"Biology of metals","url":"https://pubmed.ncbi.nlm.nih.gov/2169281","citation_count":14,"is_preprint":false},{"pmid":"20639338","id":"PMC_20639338","title":"Genetic and functional analyses of the mob operon on conjugative transposon CTn341 from Bacteroides spp.","date":"2010","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/20639338","citation_count":13,"is_preprint":false},{"pmid":"1846635","id":"PMC_1846635","title":"Effects of prostaglandin E2 and F2 alpha on cytoplasmic pH in a clonal osteoblast-like cell line, MOB 3-4.","date":"1991","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1846635","citation_count":13,"is_preprint":false},{"pmid":"2168776","id":"PMC_2168776","title":"Initial responses of a clonal osteoblast-like cell line, MOB 3-4, to phosphatidic acid in vitro.","date":"1990","source":"Bone and mineral","url":"https://pubmed.ncbi.nlm.nih.gov/2168776","citation_count":13,"is_preprint":false},{"pmid":"19074386","id":"PMC_19074386","title":"The r1162 mob proteins can promote conjugative transfer from cryptic origins in the bacterial chromosome.","date":"2008","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/19074386","citation_count":13,"is_preprint":false},{"pmid":"9473631","id":"PMC_9473631","title":"Characterisation of the mob locus from Rhodobacter sphaeroides required for molybdenum cofactor biosynthesis.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9473631","citation_count":12,"is_preprint":false},{"pmid":"2777755","id":"PMC_2777755","title":"Aluminum enhances the stimulatory effect of NaF on prostaglandin E2 synthesis in a clonal osteoblast-like cell line, MOB 3-4, in vitro.","date":"1989","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2777755","citation_count":11,"is_preprint":false},{"pmid":"33255245","id":"PMC_33255245","title":"MOB: Pivotal Conserved Proteins in Cytokinesis, Cell Architecture and Tissue 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11479704","citation_count":7,"is_preprint":false},{"pmid":"12353928","id":"PMC_12353928","title":"MOB-1 and TNF-alpha interact to induce microvascular lung injury.","date":"2002","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/12353928","citation_count":6,"is_preprint":false},{"pmid":"15315164","id":"PMC_15315164","title":"Involvement of M3 cholinergic receptor signal transduction pathway in regulation of the expression of chemokine MOB-1, MCP-1 genes in pancreatic acinar cells.","date":"2004","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/15315164","citation_count":6,"is_preprint":false},{"pmid":"27286821","id":"PMC_27286821","title":"Mob/oriT, a mobilizable site-specific recombination system for unmarked genetic manipulation in Bacillus thuringiensis and Bacillus cereus.","date":"2016","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/27286821","citation_count":6,"is_preprint":false},{"pmid":"11735368","id":"PMC_11735368","title":"DNA cloning in Lactobacillus helveticus by the exconjugation of recombinant mob-containing plasmid constructs from strains of transformable lactic acid bacteria.","date":"2001","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/11735368","citation_count":6,"is_preprint":false},{"pmid":"2852995","id":"PMC_2852995","title":"Mobilization and transfer of Azospirillum lipoferum plasmid by the Tn5-Mob transposon into a plasmid-free Agrobacterium tumefaciens strain.","date":"1988","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/2852995","citation_count":6,"is_preprint":false},{"pmid":"39067415","id":"PMC_39067415","title":"A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential.","date":"2024","source":"Hearing research","url":"https://pubmed.ncbi.nlm.nih.gov/39067415","citation_count":5,"is_preprint":false},{"pmid":"25831888","id":"PMC_25831888","title":"[Expression of sphingomyelin synthase 1 (SGMS1) gene varies in human lung and oesophagus cancer].","date":"2014","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/25831888","citation_count":5,"is_preprint":false},{"pmid":"37536630","id":"PMC_37536630","title":"Mapping the MOB proteins' proximity network reveals a unique interaction between human MOB3C and the RNase P complex.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37536630","citation_count":5,"is_preprint":false},{"pmid":"32418908","id":"PMC_32418908","title":"Function of the MOB kinase activator-like 1 in the innate immune defense of the oriental river prawn (Macrobrachium nipponense).","date":"2020","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32418908","citation_count":5,"is_preprint":false},{"pmid":"10872085","id":"PMC_10872085","title":"Deletions of mob and tra pJP4 transfer functions after mating of Ralstonia eutropha JMP134 (pJP4) with Escherichia coli harboring F'::Tn10.","date":"2000","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10872085","citation_count":5,"is_preprint":false},{"pmid":"26065260","id":"PMC_26065260","title":"[Alternative promoters localised in SGMS1 gene introns take part in regulation of its expression in human tissues].","date":"2015","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/26065260","citation_count":4,"is_preprint":false},{"pmid":"34347361","id":"PMC_34347361","title":"The NDR kinase-MOB complex FgCot1-Mob2 regulates polarity and lipid metabolism in Fusarium graminearum.","date":"2021","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/34347361","citation_count":4,"is_preprint":false},{"pmid":"26212728","id":"PMC_26212728","title":"The Xis2d protein of CTnDOT binds to the intergenic region between the mob and tra operons.","date":"2015","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/26212728","citation_count":4,"is_preprint":false},{"pmid":"36339723","id":"PMC_36339723","title":"Manganese oxidation counteracts the deleterious effect of low temperatures on biofilm formation in Pseudomonas sp. MOB-449.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36339723","citation_count":4,"is_preprint":false},{"pmid":"25093564","id":"PMC_25093564","title":"Morphogenesis: a Mob rules from the rear.","date":"2014","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/25093564","citation_count":4,"is_preprint":false},{"pmid":"38349166","id":"PMC_38349166","title":"MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in Aspergillus fumigatus.","date":"2024","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/38349166","citation_count":3,"is_preprint":false},{"pmid":"34773620","id":"PMC_34773620","title":"PLASmid TAXonomic PCR (PlasTax-PCR), a Multiplex Relaxase MOB Typing to Assort Plasmids into Taxonomic Units.","date":"2022","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/34773620","citation_count":3,"is_preprint":false},{"pmid":"30191692","id":"PMC_30191692","title":"PECULIARITIES OF THE STRUCTURE AND EXPRESSION OF HUMAN SPHINGOMYELIN SYNTHASE 1 GENE (SGMS1).","date":"2016","source":"Tsitologiia","url":"https://pubmed.ncbi.nlm.nih.gov/30191692","citation_count":2,"is_preprint":false},{"pmid":"20171577","id":"PMC_20171577","title":"Characterization and mapping of a novel mutant sms1 (senescence and male sterility 1) in rice.","date":"2010","source":"Journal of genetics and genomics = Yi chuan xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/20171577","citation_count":2,"is_preprint":false},{"pmid":"37926998","id":"PMC_37926998","title":"SGMS1-AS1/MicroRNA-106a-5p/CPT2 Axis as a Novel Target for Regulating Lactate Metabolism in Colon Cancer.","date":"2023","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/37926998","citation_count":2,"is_preprint":false},{"pmid":"1571204","id":"PMC_1571204","title":"Effect of phorbol myristate acetate on release of arachidonic acid and its metabolites in the osteoblastic MOB 3-4 cell line and its subclone, MOB 3-4-F2.","date":"1992","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/1571204","citation_count":2,"is_preprint":false},{"pmid":"19247963","id":"PMC_19247963","title":"The mob as tumor suppressor (mats1) gene is required for growth control in developing zebrafish embryos.","date":"2009","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19247963","citation_count":2,"is_preprint":false},{"pmid":"40608153","id":"PMC_40608153","title":"When to mob? plasticity of antipredator behavior in common ravens' families (Corvus corax) across offspring development.","date":"2025","source":"Animal cognition","url":"https://pubmed.ncbi.nlm.nih.gov/40608153","citation_count":2,"is_preprint":false},{"pmid":"1652270","id":"PMC_1652270","title":"Starvation of a clonal osteoblast-like cell line, MOB 3-4-F2, down-regulates prostaglandin E2 receptors but increases cAMP response to prostaglandin E2.","date":"1991","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/1652270","citation_count":2,"is_preprint":false},{"pmid":"21647613","id":"PMC_21647613","title":"Molecular cloning, sequence characterization, and tissue expression analysis of chicken sphingomyelin synthase 1 (SMS1).","date":"2011","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21647613","citation_count":1,"is_preprint":false},{"pmid":"37314589","id":"PMC_37314589","title":"MOB kinase activator 1A acts as an oncogene by targeting PI3K/AKT/mTOR in ovarian cancer.","date":"2023","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37314589","citation_count":1,"is_preprint":false},{"pmid":"1327483","id":"PMC_1327483","title":"Chromosome mobilization of Legionella pneumophila with RK2::Mu and Tn5-Mob.","date":"1992","source":"Canadian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1327483","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45087,"output_tokens":2527,"usd":0.086583,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9021,"output_tokens":2414,"usd":0.052727,"stage2_stop_reason":"end_turn"},"total_usd":0.13931,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about SGMS1 (sphingomyelin synthase 1, also known as SMS1, MOB, TMEM23, MGC17342).\n\nThe vast majority of papers are about unrelated genes/topics:\n- MOB proteins in Hippo/NDR kinase signaling (different gene family)\n- Bacterial mob/relaxase genes (plasmid mobilization)\n- Mob-1 chemokine (IP-10/CXCL10 - different gene)\n- Mats/MATS tumor suppressor (MOB family kinase activator - different gene)\n- MOB 3-4 osteoblast cell line studies\n- MoB MBene materials science\n- Various bacterial, plant, fungal MOB genes\n\nPapers clearly about SGMS1 (sphingomyelin synthase 1):\n- PMID 17449912 (Tafesse et al., 2007) - SMS1 and SMS2 in HeLa cells\n- PMID 18820264 (Jin et al., 2008) - SMS1 knockdown in T cells\n- PMID 16226406 (Yang et al., 2005) - Mouse SMS1 gene structure/function\n- PMID 34278704 (Dong et al., 2021) - ROR2/STK4-FOXO1/SMS1 axis\n- PMID 38544565 (Yang et al., 2024) - SGMS1 in MSC osteogenic differentiation\n- PMID 39067415 (Chen et al., 2024) - Sgms1 mutation and hearing loss\n- PMID 21549185 (Rozhkova et al., 2011) - Human SMS1 gene structure\n- PMID 23063490 (Zama et al., 2012) - SMS activity assay\n- PMID 15315829 (Vladychenskaya et al., 2004) - MOB gene structure\n- PMID 30646599 (Fernández-García et al., 2019) - SMS1/SMS2 in glioma\n- PMID 21647613 (Man & Lee, 2011) - Chicken SMS1 cloning\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"SMS1 localizes to the Golgi and SMS2 localizes to the plasma membrane in HeLa cells; both function as the key SM synthases at these respective compartments. RNAi-mediated depletion of either SMS1 or SMS2 caused substantial decreases in sphingomyelin production, accumulation of ceramide, and a block in cell growth. External addition of SM did not restore growth, indicating the biological role of SMS synthases extends beyond SM formation.\",\n      \"method\": \"RNA interference (RNAi) knockdown, lipid analysis, subcellular fractionation/localization, cell growth assays in HeLa cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional data with two orthogonal methods (RNAi + lipid mass measurements + growth assays), replicated across two isoforms with clear compartmental distinction\",\n      \"pmids\": [\"17449912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMS1 knockdown in Jurkat T cells (SMS1-siRNA) severely reduced membrane sphingomyelin expression and impaired TCR signal transduction: CD3 stimulation failed to induce CD69 expression, cell adhesion, proliferation, and TCR clustering. CD3-induced tyrosine phosphorylation, LAT association with ZAP-70 and Grb2, and PKC phosphorylation were impaired. Translocation of TCR, ZAP-70, and PKC into lipid rafts was markedly decreased, indicating SMS1-produced sphingomyelin is essential for lipid raft integrity and TCR signaling.\",\n      \"method\": \"siRNA knockdown of SMS1 in Jurkat T cells, flow cytometry, immunoprecipitation, lipid raft fractionation, proliferation assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with multiple orthogonal readouts (lipid raft fractionation, signaling molecule phosphorylation, functional T cell activation assays), single lab\",\n      \"pmids\": [\"18820264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The mouse SMS1 gene is alternatively spliced to produce four mRNA transcripts (SMS1alpha1, SMS1alpha2, SMS1beta, SMS1gamma) encoding three different proteins (SMS1alpha, SMS1beta, SMS1gamma). SMS1alpha prevents Bax-induced growth inhibition in a yeast-based assay, while SMS1beta neither prevents nor enhances the effects of Bax or SMS1alpha, indicating isoform-specific functional differences. SMS1 transcripts increase in response to pro-apoptotic TNF-alpha.\",\n      \"method\": \"RT-PCR, genomic structure analysis, yeast functional complementation assay (Bax growth inhibition), Northern blot\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast functional assay with isoform comparison, multiple transcript characterization by RT-PCR, single lab with two orthogonal approaches\",\n      \"pmids\": [\"16226406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROR2 depletion in dental pulp stem cells (DPSCs) inhibits SMS1 expression and sphingomyelin biosynthesis. Mechanistically, ROR2 inhibits STK4 phosphorylation, which promotes FOXO1 nuclear translocation; nuclear FOXO1 directly binds the SMS1 promoter and represses its transcription. STK4 inhibition or FOXO1 knockdown upregulated SMS1 expression and increased SM levels, reversing the senescence phenotype. This defines a ROR2/STK4-FOXO1/SMS1 regulatory axis controlling sphingomyelin synthesis and DPSC senescence.\",\n      \"method\": \"siRNA knockdown, overexpression, ChIP (FOXO1 binding to SMS1 promoter), Western blot for phosphorylation, proliferation assays, lipid analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct FOXO1 binding to SMS1 promoter, supported by genetic epistasis (KD of pathway components), single lab\",\n      \"pmids\": [\"34278704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SGMS1 promotes osteogenic differentiation of mesenchymal stem cells (MSCs) by regulating ceramide/sphingomyelin metabolism: SGMS1 overexpression inhibits ceramide and increases sphingomyelin levels, thereby restraining PP2A activity and enhancing phosphorylated Akt, Runx2, and VEGF levels. SM treatment neutralized the suppressive effect of SGMS1 silencing on osteogenesis. SGMS1 transcription is regulated by Runx2 (feedback loop). SGMS1 promotes MSC-mediated angiogenesis via VEGF upregulation and accelerates bone regeneration in vivo.\",\n      \"method\": \"siRNA knockdown and overexpression of SGMS1, lipid measurements (ceramide/SM), Western blot (PP2A activity, pAkt, Runx2, VEGF), SM supplementation rescue experiments, in vivo rat bone regeneration model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (lipid analysis, signaling Western blots, rescue with SM, in vivo model), single lab\",\n      \"pmids\": [\"38544565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Complete knockout of Sgms1 (exon 7 deletion, Sgms1tm1b) in mice causes progressive hearing loss with a consistently reduced endocochlear potential (~80 mV vs ~120 mV in controls). The stria vascularis showed irregular marginal cell surfaces and patchy loss of Kcnq1 expression, with marginal cells identified as the likely initial site of dysfunction. A partial knockdown allele (20% residual transcript) was sufficient for normal hearing, indicating a threshold requirement for SMS1 in maintaining endocochlear potential.\",\n      \"method\": \"Conditional/constitutive mouse knockout (Sgms1tm1b), auditory brainstem response, endocochlear potential measurement, immunofluorescence (Kcnq1), gene expression analysis of lateral wall\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined molecular phenotype (endocochlear potential reduction), cellular localization of dysfunction (marginal cells, Kcnq1 loss), dose-response with partial knockdown allele, multiple physiological and molecular readouts\",\n      \"pmids\": [\"39067415\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SGMS1 (sphingomyelin synthase 1) is a Golgi-localized enzyme that catalyzes the transfer of phosphocholine from phosphatidylcholine to ceramide, producing sphingomyelin and diacylglycerol; its activity is required for sphingomyelin homeostasis in cellular membranes, lipid raft integrity necessary for TCR signaling, osteogenic differentiation of MSCs via a ceramide/PP2A/Akt pathway, and maintenance of the endocochlear potential in the inner ear stria vascularis marginal cells, with its transcription regulated by a ROR2/STK4-FOXO1 axis and by Runx2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SGMS1 (sphingomyelin synthase 1) is a Golgi-localized enzyme that governs cellular sphingomyelin homeostasis, partitioning the ceramide/sphingomyelin balance that underlies membrane organization and downstream signaling [#0]. Depletion of SMS1 lowers sphingomyelin and causes ceramide accumulation, blocking cell growth in a manner not rescued by exogenous sphingomyelin, indicating its role extends beyond bulk lipid supply [#0]. By supplying sphingomyelin to membrane microdomains, SMS1 is required for lipid raft integrity: its loss in T cells prevents translocation of TCR, ZAP-70, and PKC into rafts and impairs CD3-induced signaling and T cell activation [#1]. The same ceramide/sphingomyelin switch links SMS1 to differentiation programs—in mesenchymal stem cells SGMS1 lowers ceramide and restrains PP2A, enhancing phosphorylated Akt, Runx2, and VEGF to drive osteogenesis and angiogenesis, with Runx2 feeding back onto SGMS1 transcription [#4], while a ROR2/STK4–FOXO1 axis represses SGMS1 transcription through direct FOXO1 binding to its promoter [#3]. At the organ level, SGMS1 is required to maintain the endocochlear potential, where its knockout in mice produces progressive hearing loss with stria vascularis marginal cell dysfunction and patchy Kcnq1 loss, and a threshold of residual expression suffices for normal hearing [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the gene architecture of SMS1 and that its isoforms carry distinct functional outputs, opening the question of isoform-specific roles in cell survival.\",\n      \"evidence\": \"RT-PCR, genomic structure analysis, and yeast Bax-complementation assays of mouse SMS1 splice variants\",\n      \"pmids\": [\"16226406\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional readout limited to a yeast Bax-growth assay rather than mammalian cells\", \"Mechanism by which SMS1alpha prevents Bax-induced growth inhibition not defined\", \"Link between TNF-alpha induction and enzymatic activity not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined SMS1 as the Golgi-resident sphingomyelin synthase whose activity is rate-limiting for SM production and cell growth, resolving where in the cell SM is made.\",\n      \"evidence\": \"RNAi knockdown with lipid mass measurements, subcellular localization, and growth assays in HeLa cells\",\n      \"pmids\": [\"17449912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ceramide accumulation to growth arrest not resolved\", \"Catalytic mechanism and substrate kinetics not characterized in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that SMS1-derived sphingomyelin is required for lipid raft integrity and TCR signal transduction, connecting the enzyme to immune cell activation.\",\n      \"evidence\": \"siRNA knockdown in Jurkat T cells with lipid raft fractionation, immunoprecipitation, and T cell activation assays\",\n      \"pmids\": [\"18820264\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single cell line and single lab\", \"Whether the defect reflects raft composition versus a specific SM-protein interaction not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified transcriptional control of SGMS1 by a ROR2/STK4–FOXO1 axis, explaining how SM synthesis is downregulated during stem cell senescence.\",\n      \"evidence\": \"siRNA/overexpression, ChIP for FOXO1 binding to the SMS1 promoter, and phosphorylation Westerns in dental pulp stem cells\",\n      \"pmids\": [\"34278704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and single cell type\", \"Direct FOXO1 binding site sequence not mapped beyond ChIP\", \"Generality across other SGMS1-expressing tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SGMS1 within an osteogenic signaling circuit, showing it acts through the ceramide/PP2A/Akt–Runx2 pathway and forms a transcriptional feedback loop with Runx2.\",\n      \"evidence\": \"Knockdown/overexpression with lipid measurements, signaling Westerns, SM-supplementation rescue, and an in vivo rat bone regeneration model\",\n      \"pmids\": [\"38544565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic versus signaling contributions to PP2A restraint not separated\", \"Single lab\", \"Whether Runx2 binds the SGMS1 promoter directly not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated an essential, dose-dependent in vivo role for SGMS1 in maintaining the endocochlear potential, localizing its physiological requirement to stria vascularis marginal cells.\",\n      \"evidence\": \"Constitutive Sgms1 knockout mice with auditory brainstem response, endocochlear potential measurement, and Kcnq1 immunofluorescence\",\n      \"pmids\": [\"39067415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between SM synthesis and Kcnq1 maintenance not defined\", \"Whether the defect is cell-autonomous to marginal cells not established\", \"Human hearing-loss association not tested in this study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SGMS1's local ceramide/sphingomyelin switch is mechanistically transduced into distinct downstream outputs—raft-dependent signaling, PP2A/Akt control, and ion-channel maintenance—across different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the enzyme in the corpus\", \"Substrate channeling and compartment-specific lipid pools not dissected\", \"Causal chain from SM levels to specific effector proteins (KCNQ1, PP2A) not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}