Affinage

MBTPS1

Membrane-bound transcription factor site-1 protease · UniProt Q14703

Round 2 corrected
Length
1052 aa
Mass
117.7 kDa
Annotated
2026-04-28
130 papers in source corpus 11 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MBTPS1 (Site-1 Protease/SKI-1) is a Golgi-resident, membrane-bound subtilisin-like serine protease that initiates the regulated intramembrane proteolysis of multiple type II membrane-bound transcription factors, linking cholesterol/lipid homeostasis, the unfolded protein response, and innate immune signaling. S1P cleaves SREBPs in the Golgi following SCAP-dependent ER-to-Golgi transport, a sterol-regulated step that constitutes the key control point for lipid metabolism; it similarly cleaves ATF6 during ER stress in a SCAP-independent manner to activate UPR target genes (PMID:9809072, PMID:10619424, PMID:11163209). S1P also processes pro-BDNF at a non-basic RGLT↓SL motif and viral glycoproteins, distinguishing it from other proprotein convertases that require basic-residue cleavage sites (PMID:9990022, PMID:11152678). Beyond lipid regulation, S1P participates in NF-κB activation by cleaving SREBP1 within a Golgi-localized Scap–SREBP1–IκBα super-complex upon LPS stimulation, and its hypomorphic loss in mice impairs the ATF6-driven UPR in intestinal epithelial cells, causing enhanced susceptibility to colitis (PMID:37267109, PMID:19202076).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1998 High

    Identification of S1P as the initiating protease for SREBP cleavage resolved a long-sought enzymatic activity controlling cholesterol and lipid gene regulation, establishing MBTPS1 as the gatekeeper of sterol-responsive proteolysis.

    Evidence Functional complementation cloning using S1P-deficient SRD-12B CHO cells and a PLAP-BP2 secretion reporter

    PMID:9809072

    Open questions at the time
    • Subcellular site of cleavage not yet mapped
    • Substrate specificity beyond SREBPs unknown
    • Mechanism of sterol regulation of S1P activity not resolved
  2. 1999 High

    Independent identification of S1P as SKI-1, a proprotein convertase cleaving pro-BDNF at a non-basic site, expanded the enzyme's substrate repertoire beyond SREBPs and revealed that it is processed autocatalytically into multiple glycoforms localized to the Golgi and endosomal compartments.

    Evidence In vitro cleavage assays of pro-BDNF, metabolic labeling and immunoprecipitation, and immunocytochemistry of stably transfected HK293 cells

    PMID:9990022

    Open questions at the time
    • Cleavage-site determinants for non-basic substrates not defined
    • Functional significance of shed 98-kDa ectodomain unknown
  3. 1999 High

    Demonstrating that SCAP-dependent ER-to-Golgi transport is the sterol-regulated step—not S1P activity itself—resolved how cells restrict SREBP processing to sterol-depleted conditions; relocating S1P to the ER bypassed SCAP and made cleavage constitutive.

    Evidence Brefeldin A treatment and KDEL-S1P ER-retention fusion constructs in SCAP-deficient cells

    PMID:10619424

    Open questions at the time
    • Mechanism of SCAP sterol sensing not addressed
    • Whether other substrates also require regulated transport to the Golgi unknown
  4. 2000 High

    Showing that S1P and S2P are both required for ATF6 cleavage during ER stress—but independently of SCAP—established S1P as a shared effector protease linking lipid homeostasis and the UPR through distinct upstream regulatory mechanisms.

    Evidence Cell-based proteolysis assays in S1P- and S2P-deficient mutant CHO lines, site-directed mutagenesis of ATF6 cleavage motifs

    PMID:11163209

    Open questions at the time
    • Mechanism by which ATF6 reaches the Golgi without SCAP not identified
    • Whether S1P directly senses ER stress or only acts constitutively in the Golgi unclear
  5. 2001 High

    Precise mapping of the pro-BDNF cleavage site (R54) and demonstration that S1P cleavage produces a 28-kDa intermediate—not an obligatory precursor for mature BDNF—clarified the processing hierarchy of pro-BDNF through sequential convertases.

    Evidence R54A site-directed mutagenesis and furin inhibitor α1-PDX in a vaccinia virus expression system with metabolic labeling

    PMID:11152678

    Open questions at the time
    • Physiological role of the 28-kDa intermediate in vivo not established
    • Whether S1P processes other neurotrophins unknown
  6. 2002 High

    Domain mapping of ATF6 identified separate luminal determinants for ER-stress sensing/Golgi translocation (CD1) and S1P cleavage (CD2), establishing that stress sensing and proteolytic processing are mechanistically separable events.

    Evidence ATF6 deletion constructs and chimeric ATF6-LZIP fusions with ER stress assays and localization studies

    PMID:11821395

    Open questions at the time
    • Identity of the ER-stress sensor interacting with CD1 not determined
    • Structural basis of S1P recognition of the CD2 domain unknown
  7. 2009 High

    An in vivo hypomorphic Mbtps1 mutation revealed that S1P is non-redundantly required for the ATF6-dependent UPR in intestinal epithelial cells, providing the first genetic evidence that diminished S1P activity predisposes to colitis through defective ER chaperone induction.

    Evidence ENU-induced missense Mbtps1 mutation in mice, DSS colitis model, bone marrow chimera experiments, Western blot for GRP78/GRP94

    PMID:19202076

    Open questions at the time
    • Precise residue affected by ENU mutation and its structural consequence not detailed here
    • Whether SREBP-dependent lipid pathways also contribute to the colitis phenotype not resolved
    • Human disease relevance of MBTPS1 loss-of-function in IBD not established
  8. 2023 High

    Discovery that Scap–SREBP1–IκBα form a super-complex tethering NF-κB near the ER, and that S1P-mediated cleavage of SREBP1 at the Golgi liberates IκBα for IKK phosphorylation, uncovered a previously unknown role for the lipogenesis cascade in spatiotemporal NF-κB activation upon LPS stimulation.

    Evidence Co-immunoprecipitation of Scap-SREBP1-IκBα complex, Scap and SREBP1 genetic knockouts, S1P/S2P pharmacological inhibition, LPS stimulation, NF-κB reporter assays

    PMID:37267109

    Open questions at the time
    • Whether this NF-κB mechanism operates in non-macrophage cell types not shown
    • Direct structural evidence for the ternary Scap-SREBP1-IκBα complex lacking
    • Whether S1P cleavage of SREBP1 in this context differs kinetically from sterol-regulated processing unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis for S1P's unusual non-basic substrate specificity, whether S1P has additional physiological substrates beyond SREBPs/ATF6/BDNF/viral glycoproteins, and the in vivo significance of the shed 98-kDa ectodomain form in the secretory pathway.
  • No crystal structure of S1P catalytic domain with substrate resolved
  • Full in vivo substrate repertoire not systematically defined
  • Functional role of shed S1P ectodomain unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005794 Golgi apparatus 4 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-162582 Signal Transduction 1
Partners
ATF6BDNFMBTPS2SCAPSREBF1SREBF2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MBTPS1 (Site-1 Protease, S1P) was molecularly identified as a 1052-amino-acid membrane-bound subtilisin-like serine protease that cleaves SREBPs in the ER luminal loop. Cloning was achieved by functional complementation of SRD-12B cells (S1P-deficient CHO cholesterol auxotrophs) using a PLAP-BP2 reporter construct; S1P expression restored Site-1 cleavage and PLAP secretion. S1P is sterol-regulated and is the initiating protease controlling lipid metabolism in animal cells. Functional complementation cloning in S1P-deficient SRD-12B cells, PLAP secretion reporter assay, cDNA transfection Molecular cell High 9809072
1999 MBTPS1 (SKI-1) was independently identified as a widely expressed type I membrane-bound proprotein convertase with subtilisin/kexin-like serine protease activity. It cleaves pro-BDNF at an RGLT↓SL bond generating a 28-kDa product from the 32-kDa precursor. SKI-1 is processed in the ER into 120-kDa and 106-kDa membrane-bound forms differing in N-glycosylation, and a shed 98-kDa form appears late in the secretory pathway. Immunocytochemistry showed localization to the Golgi apparatus and punctate endosome-like structures. RT-PCR cloning, in vitro cleavage assay of pro-BDNF, metabolic labeling, immunoprecipitation, immunocytochemistry of stably transfected HK293 cells Proceedings of the National Academy of Sciences of the United States of America High 9990022
1999 MBTPS1-mediated proteolysis of SREBPs is transport-dependent: SCAP escorts SREBPs from the ER to the Golgi where S1P cleaves them. Relocating active S1P from Golgi to ER (by brefeldin A treatment or by fusing the KDEL ER-retention signal to S1P) bypasses the SCAP requirement and renders SREBP cleavage sterol-insensitive. This demonstrated that S1P normally resides in and acts at the Golgi, and that regulated ER-to-Golgi transport of the SCAP-SREBP complex is the key control point. Brefeldin A treatment, KDEL-S1P fusion construct, cell-based SREBP cleavage assays, genetic complementation with SCAP-deficient cells Cell High 10619424
2000 MBTPS1 (S1P) and Site-2 protease (S2P) are required for ER stress-induced cleavage of ATF6, a membrane-bound transcription factor that activates the unfolded protein response. ATF6 processing was completely blocked in S2P-deficient cells and partially blocked in S1P-deficient cells. ATF6 processing required the same RxxL and Asn/Pro sequence motifs needed for SREBP processing by S1P/S2P. Unlike SREBP processing, ATF6 processing did not require SCAP. Cell-based proteolysis assays in S1P- and S2P-deficient mutant cell lines, site-directed mutagenesis of ATF6 cleavage motifs, GRP78 induction assay Molecular cell High 11163209
2001 MBTPS1 (SKI-1) cleaves pro-BDNF at the Arg-Gly-Leu-Thr↓Ser-Leu site in the ER/trans-Golgi network to generate a 28-kDa intermediate. Mutation of Arg54 to Ala abolished this cleavage. The 28-kDa form is not an obligatory intermediate for mature 14-kDa BDNF generation; blocking furin-like enzymes (with α1-PDX) abolishes mature BDNF but does not cause 28-kDa accumulation. Vaccinia virus expression system, metabolic labeling, immunoprecipitation, in vitro mutagenesis (R54A), furin inhibitor (α1-PDX) The Journal of biological chemistry High 11152678
2002 ATF6 is transported from the ER to the Golgi in response to ER stress, where it is cleaved in its luminal domain by MBTPS1 (Site-1 protease). The conserved CD1 region of ATF6's luminal domain is required for ER-to-Golgi translocation, while the CD2 region is required for S1P cleavage. The ATF6 luminal domain alone is sufficient to sense ER stress and cause Golgi translocation when fused to another ER transmembrane protein (LZIP). ATF6 domain deletion and chimeric fusion constructs (ATF6-LZIP), cell-based ER stress assays, subcellular localization studies The Journal of biological chemistry High 11821395
2009 A hypomorphic ENU-induced missense mutation in Mbtps1 (encoding S1P) causes enhanced susceptibility to DSS-induced colitis in mice. The mutation diminishes S1P's non-redundant role in the ATF6-dependent unfolded protein response, resulting in reduced levels of ER chaperones GRP78 (BiP) and GRP94 in the colon upon DSS challenge. Bone marrow chimera experiments established that the S1P requirement is in non-hematopoietic cells. ENU mutagenesis screen, DSS colitis model, bone marrow chimera experiments, Western blot for ER chaperones (GRP78, GRP94) Proceedings of the National Academy of Sciences of the United States of America High 19202076
2008 MBTPS1 (SKI-1/S1P) belongs to the subtilisin/kexin-like serine protease superfamily and is classified within a distinct subfamily. Its catalytic domain shares the conserved Asp, His, Ser catalytic triad of subtilases. SKI-1 is distinguished by cleavage at non-basic residues (e.g., hydrophobic/small residues at P1), contrasting with the basic-residue specificity of other proprotein convertases. Comparative sequence analysis, multiple sequence alignment, 3D homology modeling of catalytic domain Protein science : a publication of the Protein Society Medium 9070434
2008 MBTPS1 (SKI-1/S1P) is one of nine mammalian secretory serine proteases of the subtilisin type. Together with PCSK9, it forms a subclass that cleaves at non-basic residues and regulates cholesterol and lipid homeostasis. SKI-1/S1P activates SREBPs and ATF6 among other substrates, and processes viral glycoproteins. It is considered an attractive therapeutic target. Review integrating biochemical, genetic, and pharmacological data from multiple experimental systems Nature reviews. Drug discovery Medium 22679642
2008 MBTPS1 (SKI-1/S1P) is activated in the ER by autocatalytic removal of its prodomain, generating the 120-kDa and 106-kDa membrane-bound active forms, followed by shedding of the 98-kDa ectodomain into the secretory pathway. The convertase is enriched in the Golgi and endosomal compartments and exhibits a broad substrate range including SREBPs, ATF6, CREB/ATF family members, and viral glycoproteins. Review synthesizing biochemical processing assays, cell-based localization experiments, and substrate identification studies The international journal of biochemistry & cell biology Medium 18343183
2023 The lipogenesis cascade Scap-SREBP1-S1P/S2P orchestrates the spatiotemporal activation of NF-κB. Scap and SREBP1 form a super-complex with IκBα to tether NF-κB near the ER. Upon LPS stimulation, Scap transports the complex to the Golgi where MBTPS1 (S1P) cleaves SREBP1, liberating IκBα for IKK-mediated phosphorylation and NF-κB activation. Loss of Scap or inhibition of S1P/S2P diminishes LPS-induced NF-κB activation; SREBP1 deficiency augments it. Genetic knockouts and siRNA knockdown of Scap, SREBP1; pharmacological S1P/S2P inhibition; co-immunoprecipitation of Scap-SREBP1-IκBα super-complex; LPS stimulation assays; NF-κB reporter assays Cell reports High 37267109

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2000 ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Molecular cell 1503 11163209
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
2009 Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate. Science (New York, N.Y.) 832 19729656
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1997 Subtilases: the superfamily of subtilisin-like serine proteases. Protein science : a publication of the Protein Society 698 9070434
2005 Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science (New York, N.Y.) 664 16151014
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2012 The biology and therapeutic targeting of the proprotein convertases. Nature reviews. Drug discovery 649 22679642
2001 Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. The Journal of biological chemistry 443 11152678
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2004 Structural and functional characteristics of S1P receptors. Journal of cellular biochemistry 405 15258915
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2002 The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. The Journal of biological chemistry 388 11821395
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1998 Molecular identification of the sterol-regulated luminal protease that cleaves SREBPs and controls lipid composition of animal cells. Molecular cell 333 9809072
2002 Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. Journal of lipid research 302 12177166
2012 The endoplasmic reticulum stress response in aging and age-related diseases. Frontiers in physiology 298 22934019
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
1999 Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 276 10619424
2012 Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. Developmental cell 263 22975328
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2008 The activation and physiological functions of the proprotein convertases. The international journal of biochemistry & cell biology 253 18343183
2006 Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling. The EMBO journal 249 17124500
1999 Mammalian subtilisin/kexin isozyme SKI-1: A widely expressed proprotein convertase with a unique cleavage specificity and cellular localization. Proceedings of the National Academy of Sciences of the United States of America 241 9990022
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2003 The structure of importin-beta bound to SREBP-2: nuclear import of a transcription factor. Science (New York, N.Y.) 182 14645851
2016 Sphingosine-1-Phosphate (S1P) and S1P Signaling Pathway: Therapeutic Targets in Autoimmunity and Inflammation. Drugs 170 27318702
2008 The vascular S1P gradient-cellular sources and biological significance. Biochimica et biophysica acta 165 18674637
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2017 Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 161 28538737
2015 Exit Strategies: S1P Signaling and T Cell Migration. Trends in immunology 133 26596799
2007 Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends in immunology 129 17276731
2007 HDL serves as a S1P signaling platform mediating a multitude of cardiovascular effects. Journal of lipid research 124 17698855
2010 Sphingosine 1-phosphate (S1P)/S1P receptors are involved in human liver fibrosis by action on hepatic myofibroblasts motility. Journal of hepatology 119 21145832
2009 Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proceedings of the National Academy of Sciences of the United States of America 117 19202076
2013 Second generation S1P pathway modulators: research strategies and clinical developments. Biochimica et biophysica acta 109 24239768
2020 Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke. Circulation research 100 33301355
2020 Finding a Way Out: S1P Signaling and Immune Cell Migration. Annual review of immunology 98 32340572
2017 An engineered S1P chaperone attenuates hypertension and ischemic injury. Science signaling 93 28811382
2012 A potent and selective S1P(1) antagonist with efficacy in experimental autoimmune encephalomyelitis. Chemistry & biology 93 22999882
2014 Atheroprotective role of high-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P). Cardiovascular research 90 24891400
2014 S1P signaling: new therapies and opportunities. F1000prime reports 88 25580263
2015 HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications. Frontiers in pharmacology 83 26539121
2012 Shaping the landscape: metabolic regulation of S1P gradients. Biochimica et biophysica acta 76 22735358
2007 Effects of LPA and S1P on the nervous system and implications for their involvement in disease. Current drug targets 76 17266539
2018 Sphingolipids in neurodegeneration (with focus on ceramide and S1P). Advances in biological regulation 74 30287225
2021 Monocyte-derived S1P in the lymph node regulates immune responses. Nature 66 33658712
2007 S1P stimulates chemotactic migration and invasion in OVCAR3 ovarian cancer cells. Biochemical and biophysical research communications 66 17349972
2011 Dissecting the role of the S1P/S1PR axis in health and disease. Journal of dental research 64 21248363
2006 Homo- and hetero-dimerization of LPA/S1P receptors, OGR1 and GPR4. Biochimica et biophysica acta 64 17023202
2019 The Role of S1P and the Related Signaling Pathway in the Development of Tissue Fibrosis. Frontiers in pharmacology 61 30687087
2018 Quercetin ameliorates pulmonary fibrosis by inhibiting SphK1/S1P signaling. Biochemistry and cell biology = Biochimie et biologie cellulaire 61 29940125
2017 Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation. Pain 61 28570482
2018 S1P Stimulates Proliferation by Upregulating CTGF Expression through S1PR2-Mediated YAP Activation. Molecular cancer research : MCR 60 29903770
2008 Modulating tone: the overture of S1P receptor immunotherapeutics. Immunological reviews 59 18613839
2020 The S1P-S1PR Axis in Neurological Disorders-Insights into Current and Future Therapeutic Perspectives. Cells 58 32580348
2012 The functional roles of S1P in immunity. Journal of biochemistry 58 22923732
2012 Novel selective allosteric and bitopic ligands for the S1P(3) receptor. ACS chemical biology 58 22971058
2009 S1P/S1P1 signaling stimulates cell migration and invasion in Wilms tumor. Cancer letters 58 19131156
2016 Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase. Advances in biological regulation 57 27720306
2019 Decreased S1P and SPHK2 are involved in pancreatic acinar cell injury. Biomarkers in medicine 56 31157539
2021 Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β. Cellular signalling 55 34438016
2010 S1P metabolism in cancer and other pathological conditions. Biochimie 54 20167244
2017 Sphingosine 1-phosphate (S1P) signaling in glioblastoma multiforme-A systematic review. International journal of molecular sciences 53 29149079
2007 Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression. Expert reviews in molecular medicine 53 17935635
2008 Sphingosine-1-phosphate (S1P) is a novel fibrotic mediator in the eye. Experimental eye research 52 18687328
2005 Expression of SphK1 impairs degranulation and motility of RBL-2H3 mast cells by desensitizing S1P receptors. Blood 52 15741218
2016 To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacological research 50 27663260
2014 Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors. Glia 48 24810969
2011 Role of FAK in S1P-regulated endothelial permeability. Microvascular research 45 21925517
2002 Homodimerization and heterodimerization of S1P/EDG sphingosine-1-phosphate receptors. Biochimica et biophysica acta 45 12069814
2019 Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke. Scientific reports 43 31165772
2017 S1P1 deletion differentially affects TH17 and Regulatory T cells. Scientific reports 43 29018225
2016 SIRT1 mediates Sphk1/S1P-induced proliferation and migration of endothelial cells. The international journal of biochemistry & cell biology 40 26923291
2016 Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2. Scientific reports 37 27160553
2014 Mesenchymal stromal cell secreted sphingosine 1-phosphate (S1P) exerts a stimulatory effect on skeletal myoblast proliferation. PloS one 35 25264785
2022 Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension. The Journal of clinical investigation 34 35104805
2019 S1P-S1PR1 Signaling: the "Sphinx" in Osteoimmunology. Frontiers in immunology 34 31293578
2010 Pharmacological tools for lysophospholipid GPCRs: development of agonists and antagonists for LPA and S1P receptors. Acta pharmacologica Sinica 30 20729877
2010 Roles for lysophospholipid S1P receptors in multiple sclerosis. Critical reviews in biochemistry and molecular biology 29 20979571
2021 Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling. International journal of molecular sciences 28 34445695
2017 Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties. Pharmacology research & perspectives 28 29226621
2023 The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB. Cell reports 27 37267109
2015 Role of sphingosine kinase/S1P axis in ECM remodeling of cardiac cells elicited by relaxin. Molecular endocrinology (Baltimore, Md.) 27 25415609
2021 Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis. Biomedicines 26 34829748
2020 S1P and plasmalogen derived fatty aldehydes in cellular signaling and functions. Biochimica et biophysica acta. Molecular and cell biology of lipids 26 32171908
2020 Neutrophil recruitment mediated by sphingosine 1-phosphate (S1P)/S1P receptors during chronic liver injury. Cellular immunology 26 33197723
2017 Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and potential therapeutic target for bone repair. Pharmacological research 26 28855094
2017 S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling. Mediators of inflammation 26 29333002
2023 S1P/S1PR signaling pathway advancements in autoimmune diseases. Biomolecules & biomedicine 25 37504219
2020 Relationship between Sphk1/S1P and microRNAs in human cancers. Biotechnology and applied biochemistry 25 32275078
2010 The sphingosine 1-phosphate (S1P) signaling pathway is regulated during pregnancy in sheep. Biology of reproduction 25 20107206
2020 Sphingosine-1-phosphate (S1P) receptors: Promising drug targets for treating bone-related diseases. Journal of cellular and molecular medicine 24 32155312
2020 SARS-CoV-2 Infection: A Role for S1P/S1P Receptor Signaling in the Nervous System? International journal of molecular sciences 24 32942748
2019 Emerging Connections of S1P-Metabolizing Enzymes with Host Defense and Immunity During Virus Infections. Viruses 24 31783527
2024 Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis. Journal of translational medicine 23 38200582
2021 The apoM/S1P Complex-A Mediator in Kidney Biology and Disease? Frontiers in medicine 23 34722589
2019 Pro-Inflammatory Role of S1P3 in Macrophages. Biomolecules & therapeutics 23 30917625
2012 S1P lyase in skeletal muscle regeneration and satellite cell activation: exposing the hidden lyase. Biochimica et biophysica acta 22 22750505
2018 Validating a Selective S1P1 Receptor Modulator Syl930 for Psoriasis Treatment. Biological & pharmaceutical bulletin 21 29415945
2018 Anti-CD69 therapy induces rapid mobilization and high proliferation of HSPCs through S1P and mTOR. Leukemia 21 29483712
2011 To stay or to leave: Stem cells and progenitor cells navigating the S1P gradient. World journal of biological chemistry 21 21472036
2023 Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon. Molecular and cellular biochemistry 20 36652045
2019 Sphingosine-1-phosphate (S1P) in ovarian physiology and disease. Annales d'endocrinologie 20 31455516
2024 Rewiring Endothelial Sphingolipid Metabolism to Favor S1P Over Ceramide Protects From Coronary Atherosclerosis. Circulation research 19 38456287
2021 Erythrocytes efficiently utilize exogenous sphingosines for S1P synthesis and export via Mfsd2b. The Journal of biological chemistry 19 33334894
2021 Lessons from S1P receptor targeting in multiple sclerosis. Pharmacology & therapeutics 19 34450231
2017 S1P Provokes Tumor Lymphangiogenesis via Macrophage-Derived Mediators Such as IL-1β or Lipocalin-2. Mediators of inflammation 19 28804221
2023 Force-Loaded Cementocytes Regulate Osteoclastogenesis via S1P/S1PR1/Rac1 Axis. Journal of dental research 18 37735908
2022 Ponesimod inhibits astrocyte-mediated neuroinflammation and protects against cingulum demyelination via S1P1 -selective modulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 34986275
2022 Structural basis for receptor selectivity and inverse agonism in S1P5 receptors. Nature communications 18 35961984
2019 S1P/S1P Receptor Signaling in Neuromuscolar Disorders. International journal of molecular sciences 18 31861214
2018 Ceramide and S1P Signaling in Embryonic Stem Cell Differentiation. Methods in molecular biology (Clifton, N.J.) 18 28540559
2002 EDG receptors and hepatic pathophysiology of LPA and S1P: EDG-ology of liver injury. Biochimica et biophysica acta 18 12069835
2023 S1PR1/S1PR3-YAP signaling and S1P-ALOX15 signaling contribute to an aggressive behavior in obesity-lymphoma. Journal of experimental & clinical cancer research : CR 17 36600310
2023 A virally encoded GPCR drives glioblastoma through feed-forward activation of the SK1-S1P1 signaling axis. Science signaling 17 37582160
2016 Therapeutic Strategies and Pharmacological Tools Influencing S1P Signaling and Metabolism. Medicinal research reviews 17 27480072
2013 Novel S1P(1) receptor agonists--part 3: from thiophenes to pyridines. Journal of medicinal chemistry 17 24367923
2022 ELOVL6 deficiency aggravates allergic airway inflammation through the ceramide-S1P pathway in mice. The Journal of allergy and clinical immunology 16 36592705
2020 The ceramide-S1P pathway as a druggable target to alleviate peripheral neuropathic pain. Expert opinion on therapeutic targets 16 32589067
2020 Recent advances of the function of sphingosine 1-phosphate (S1P) receptor S1P3. Journal of cellular physiology 16 33410533
2019 Attenuation of murine sclerodermatous models by the selective S1P1 receptor modulator cenerimod. Scientific reports 16 30679645
2017 Sphingosine 1-phosphate (S1P) suppresses the collagen-induced activation of human platelets via S1P4 receptor. Thrombosis research 16 28609704
2023 Altered Smooth Muscle Cell Histone Acetylome by the SPHK2/S1P Axis Promotes Pulmonary Hypertension. Circulation research 15 37698017