Sphingosine kinase 1 (SPHK1) is a diacylglycerol-kinase-like lipid kinase that phosphorylates the free sphingoid base sphingosine (and, less efficiently, sphinganine/dihydrosphingosine) using ATP to produce sphingosine 1-phosphate (S1P), a bioactive signaling lipid with both intracellular and extracellular (receptor-mediated) actions. The enzyme requires Mg2+ and has a two-domain DAGK-like fold with the catalytic cleft between the domains and a hydrophobic lipid-binding pocket; Asp81 is the catalytic proton donor/acceptor. SPHK1 is largely cytosolic but translocates to the plasma membrane upon activation, which is driven by ERK1/2-mediated phosphorylation at Ser225 and by CIB1 in a calcium-dependent manner; it also binds calmodulin and anionic (negatively charged) membranes with a preference for high positive curvature, and shuttles between cytoplasm and nucleus via CRM1-dependent nuclear export. By generating S1P, SPHK1 lowers intracellular ceramide and drives pro-survival, proliferative, pro-angiogenic and pro-inflammatory programs (for example S1P is an intracellular cofactor for the TRAF2 E3 ubiquitin ligase in TNF/NF-kappaB signaling), and it is frequently oncogenic. SPHK1 is also recruited to early endocytic intermediates, clathrin-coated pits and presynaptic terminals and participates in endocytic membrane trafficking, partly independently of its kinase activity. In neurons it has an additional acetyl-CoA-dependent serine acetyltransferase activity toward COX2/PTGS2 (characterized primarily in mouse).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008481 sphingosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetic (IBA) inference of sphingosine kinase activity, corroborated by extensive experimental evidence and the crystal structure. |
| GO:0030100 regulation of endocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SPHK1 is recruited to early endocytic intermediates and participates in endocytic membrane trafficking, so this IBA term is supported by direct experimental evidence in human. It is a downstream/context role rather than the core catalytic function; keep as non-core. |
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: S1P produced by SPHK1 promotes cell survival/inhibits apoptosis, a well-documented consequence of its enzymatic activity. This is a downstream physiological consequence, not the core molecular function. |
| GO:0046512 sphingosine biosynthetic process | IBA GO_REF:0000033 | MODIFY | Summary: This term is the biosynthesis of the sphingosine base itself, but SPHK1 consumes sphingosine to make S1P rather than synthesizing sphingosine. The more accurate process term is sphingosine metabolic process / S1P biosynthesis. Modify to sphingosine metabolic process. Proposed replacements: sphingosine metabolic process |
| GO:0071363 cellular response to growth factor stimulus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SPHK1 is activated downstream of growth factor signaling (e.g. VEGF, EGF). A plausible but non-core, downstream regulatory context. |
| GO:0003376 sphingosine-1-phosphate receptor signaling pathway | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inter-ontology inference from the sphingosine-1-phosphate receptor activity annotation. SPHK1 produces the S1P ligand and acts upstream of S1P receptor signalling rather than within it. Reason: This process term is inferred automatically from the sphingosine-1-phosphate receptor activity annotation, which this review marks as an over-annotation rather than removes, and it follows that row. SPHK1 produces the ligand that activates S1P receptors, so it acts upstream of the receptor signalling pathway without being a component of it; the inferred term over-states that upstream role. It is marked as an over-annotation rather than removed. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Nuclear localization is supported by experimental EXP annotations (nuclear shuttling via CRM1-dependent export). Non-core relative to the cytosolic/plasma-membrane catalytic sites. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: SPHK1 is predominantly cytoplasmic/cytosolic. Consistent with experimental evidence. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SPHK1 translocates to the plasma membrane on activation. Supported by IDA evidence. |
| GO:0005905 clathrin-coated pit | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Supported by direct experimental evidence (SPHK1 recruited to clathrin-coated pits and early endocytic intermediates). Non-core localization. |
| GO:0008481 sphingosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function (IEA duplicate of the experimentally supported annotation). |
| GO:0010008 endosome membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Endosome/endosome-membrane localization is supported by experimental EXP evidence. Non-core. |
| GO:0016301 kinase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO generic kinase activity. Correct but far less informative than the specific sphingosine kinase activity term. |
| GO:0019216 regulation of lipid metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA electronic annotation. Very general; SPHK1 is directly a sphingolipid metabolic enzyme, so the specific metabolic-process terms are preferable. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation; broadly consistent with endocytic-vesicle localization but less specific than the experimentally supported terms. |
| GO:0038036 sphingosine-1-phosphate receptor activity | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA electronic annotation of sphingosine-1-phosphate receptor activity. SPHK1 produces the S1P ligand and is not a receptor; treated like the mutant-phenotype row for the same term. Reason: The same term is marked as an over-annotation on the mutant-phenotype row of this review, and the claim is the same here. SPHK1 is the kinase that produces sphingosine 1-phosphate, the ligand of the S1P receptors, so it acts upstream of receptor activation and is not itself a receptor; the term attributes the receptor's activity to the enzyme that makes its ligand. Rows that share a term are judged alike, so the machine-generated row is marked in the same way rather than removed. |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: SPHK1 is enriched in nerve terminals/presynapse (SynGO-curated presynapse annotations exist). Non-core localization. |
| GO:0046512 sphingosine biosynthetic process | IEA GO_REF:0000117 | MODIFY | Summary: As with the IBA copy, this term describes synthesis of the sphingosine base, whereas SPHK1 consumes sphingosine to produce S1P. Better replaced by sphingosine metabolic process. Proposed replacements: sphingosine metabolic process |
| GO:0051049 regulation of transport | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Very general ARBA annotation. SPHK1's trafficking roles are better captured by regulation of endocytosis/endosomal fusion terms. |
| GO:0051239 regulation of multicellular organismal process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Extremely general ARBA grouping term with little annotation value. |
| GO:0071363 cellular response to growth factor stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA duplicate of the IBA growth-factor-response annotation. Plausible but non-core. |
| GO:0005515 protein binding | IPI PMID:12080051 Cloning and characterization of a protein kinase A anchoring... | MARK AS OVER ANNOTATED | Summary: IntAct IPI capturing interaction with SPHKAP/SKIP (Q2M3C7), a negative regulator of SPHK1 activity. Bare "protein binding" is uninformative as a molecular function; the interaction is real but over-annotated at this level. |
| GO:0005515 protein binding | IPI PMID:16888242 FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory in... | MARK AS OVER ANNOTATED | Summary: IntAct IPI for interaction with FHL2/SLIM3 (Q14192), an inhibitor of SPHK1 in cardiomyocytes. Bare "protein binding" is uninformative; over-annotated. |
| GO:0005515 protein binding | IPI PMID:17064696 Sphingosine kinase-1 is cleaved by cathepsin B in vitro: ide... | MARK AS OVER ANNOTATED | Summary: IntAct IPI for interaction with cathepsin B (CTSB, P07858), which cleaves SPHK1 in vitro. Bare "protein binding" is uninformative; over-annotated. |
| GO:0005515 protein binding | IPI PMID:17124500 Sphingosine 1-phosphate as a regulator of osteoclast differe... | MARK AS OVER ANNOTATED | Summary: IntAct IPI (with/from TRAF6, Q9Y4K3) arising from the RANKL/osteoclast study. Bare "protein binding" is uninformative; over-annotated. |
| GO:0005515 protein binding | IPI PMID:20838377 Guanine nucleotides regulate sphingosine kinase 1 activation... | MARK AS OVER ANNOTATED | Summary: IntAct IPI for interaction with EEF1A1 (P68104), which directly enhances SPHK1 catalytic activity. The interaction is functionally meaningful but bare "protein binding" is uninformative; over-annotated. |
| GO:0016407 acetyltransferase activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic ortholog transfer from mouse Sphk1 (Q8CI15) of a serine acetyltransferase (COX2/PTGS2) activity. This is a genuine, if secondary, moonlighting activity in neurons but is only supported By similarity in human. Keep as non-core. |
| GO:0030100 regulation of endocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer; the same term is independently supported by human IDA evidence. Non-core. |
| GO:0030139 endocytic vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer of endocytic-vesicle localization; consistent with human ISS/IDA endocytic evidence. Non-core. |
| GO:0035924 cellular response to vascular endothelial growth factor stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer; independently supported by human IDA (PMID:25417698, VEGF/SphK pathway). Non-core downstream context. |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Anti-apoptotic effect via S1P; consequence of enzymatic activity, non-core. |
| GO:0050764 regulation of phagocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer relating to microglial phagocytosis in the neuronal COX2-acetylation/neuroinflammation context. By-similarity, non-core. |
| GO:0098793 presynapse | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Presynaptic localization also supported by SynGO IDA/IMP curation. Non-core. |
| GO:0150077 regulation of neuroinflammatory response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer; neuroinflammation role via neuronal COX2 acetylation (mouse). By-similarity downstream role, non-core. |
| GO:1900060 negative regulation of ceramide biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer; independently supported by human IDA (PMID:16118219, SphK1 lowers ceramide, opposite to SphK2). A direct metabolic consequence of consuming sphingosine; non-core. |
| GO:1903978 regulation of microglial cell activation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer from mouse; part of the neuronal COX2/ neuroinflammation program. By-similarity, non-core. |
| GO:1905364 regulation of endosomal vesicle fusion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl ortholog transfer; SPHK1 acts in later endosomal maturation/membrane fusion (partly kinase-independent). Non-core trafficking role. |
| GO:0030148 sphingolipid biosynthetic process | TAS Reactome:R-HSA-1660661 | ACCEPT | Summary: Reactome pathway annotation placing SPHK1 in sphingolipid biosynthesis (production of S1P). Correct and relevant to the core metabolic function. |
| GO:0008481 sphingosine kinase activity | TAS Reactome:R-HSA-5218845 | ACCEPT | Summary: Reactome TAS of the core sphingosine kinase activity. |
| GO:0008481 sphingosine kinase activity | TAS Reactome:R-HSA-9625814 | ACCEPT | Summary: Reactome TAS of the core sphingosine kinase activity (estrogen-stimulated context). |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence plasma-membrane localization, consistent with activation-dependent PM translocation. |
| GO:0005634 nucleus | EXP PMID:14575709 Identification of functional nuclear export sequences in hum... | KEEP AS NON CORE | Summary: Experimental demonstration that SPHK1 shuttles between cytoplasm and nucleus via CRM1-dependent nuclear export (two functional NES). Non-core localization. |
| GO:0005634 nucleus | EXP PMID:19854831 Translocation of sphingosine kinase 1 to the plasma membrane... | KEEP AS NON CORE | Summary: Experimental nuclear localization (CIB1/translocation study). Non-core. |
| GO:0005634 nucleus | EXP PMID:29662056 Neuronal SphK1 acetylates COX2 and contributes to pathogenes... | KEEP AS NON CORE | Summary: Experimental nuclear localization (neuronal SphK1 study). Non-core. |
| GO:0005737 cytoplasm | EXP PMID:14575709 Identification of functional nuclear export sequences in hum... | ACCEPT | Summary: SPHK1 is predominantly cytoplasmic when expressed in cells (its cytoplasmic localization depends on active NES-directed nuclear export). Consistent with the primary catalytic compartment. |
| GO:0005737 cytoplasm | EXP PMID:29662056 Neuronal SphK1 acetylates COX2 and contributes to pathogenes... | ACCEPT | Summary: Experimental cytoplasmic localization (neuronal study). Consistent with core cytosolic compartment. |
| GO:0008481 sphingosine kinase activity | EXP PMID:10802064 Functional characterization of human sphingosine kinase-1. | ACCEPT | Summary: Direct functional characterization of human SPHK1 kinase activity and substrate specificity. Core molecular function. |
| GO:0008481 sphingosine kinase activity | EXP PMID:23602659 Molecular basis of sphingosine kinase 1 substrate recognitio... | ACCEPT | Summary: Crystal structures with substrate analog/ADP plus mutagenesis and kinetics establishing the catalytic mechanism. Core molecular function. |
| GO:0010008 endosome membrane | EXP PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: Experimental recruitment of SPHK1 to endocytic/endosomal membranes. Non-core localization. |
| GO:0045202 synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS synapse localization by similarity to mouse; SPHK1 is enriched in nerve terminals. Non-core; presynapse is the more specific term also annotated. |
| GO:0008481 sphingosine kinase activity | IDA PMID:21075214 A critical role for the protein phosphatase 2A B'Ξ± regulator... | ACCEPT | Summary: IDA of sphingosine kinase activity in the PP2A-dephosphorylation study. Core molecular function. |
| GO:0098793 presynapse | IDA PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: SynGO-curated presynaptic localization of SPHK1 (enriched in nerve terminals). Non-core localization. |
| GO:0098793 presynapse | IMP PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: SynGO IMP presynapse annotation (functional evidence at the presynaptic terminal). Non-core localization. |
| GO:0001727 lipid kinase activity | TAS Reactome:R-HSA-428273 | MARK AS OVER ANNOTATED | Summary: Reactome generic lipid kinase activity. Correct but subsumed by the specific sphingosine kinase activity term. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9836617 | KEEP AS NON CORE | Summary: Reactome nucleoplasm localization (PKR-mediated signaling module). Consistent with nuclear shuttling; non-core. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9836621 | KEEP AS NON CORE | Summary: Reactome nucleoplasm localization. Non-core. |
| GO:0005515 protein binding | IPI PMID:18263879 Eukaryotic elongation factor 1A interacts with sphingosine k... | MARK AS OVER ANNOTATED | Summary: IPI for interaction with EEF1A1 (P68104), which directly enhances SPHK1 catalytic activity ~3-fold. Functionally meaningful interaction, but bare "protein binding" is uninformative; over-annotated. |
| GO:0008481 sphingosine kinase activity | IDA PMID:11923095 1-O-Hexadecyl-2-desoxy-2-amino-sn-glycerol, a substrate for ... | ACCEPT | Summary: IDA of substrate specificity of purified human SPHK1 (D-erythro sphingoid bases). Core molecular function. |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:16118219 SphK1 and SphK2, sphingosine kinase isoenzymes with opposing... | KEEP AS NON CORE | Summary: SPHK1 is anti-apoptotic/pro-survival (opposite to SPHK2). Consequence of S1P production; non-core. |
| GO:1900060 negative regulation of ceramide biosynthetic process | IDA PMID:16118219 SphK1 and SphK2, sphingosine kinase isoenzymes with opposing... | KEEP AS NON CORE | Summary: SPHK1 lowers cellular ceramide (opposite to SPHK2), a direct metabolic consequence of diverting sphingosine to S1P. Non-core metabolic effect. |
| GO:0008481 sphingosine kinase activity | IDA PMID:25417698 Pathological roles of the VEGF/SphK pathway in Niemann-Pick ... | ACCEPT | Summary: IDA of SPHK1 kinase activity (VEGF/SphK pathway in Purkinje cells). Core molecular function. |
| GO:0035924 cellular response to vascular endothelial growth factor stimulus | IDA PMID:25417698 Pathological roles of the VEGF/SphK pathway in Niemann-Pick ... | KEEP AS NON CORE | Summary: SPHK1 kinase activity increases in response to VEGFA in Purkinje cells. Downstream signaling context; non-core. |
| GO:0005905 clathrin-coated pit | IDA PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: Direct experimental localization of SPHK1 to clathrin-coated pits/early endocytic intermediates. Non-core localization. |
| GO:0008289 lipid binding | IDA PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: SPHK1 binds negatively charged (anionic) membranes with a preference for high positive curvature, mediating its membrane recruitment. A real molecular property that supports membrane targeting; keep as non-core relative to the catalytic activity. |
| GO:0008481 sphingosine kinase activity | IDA PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | ACCEPT | Summary: IDA of SPHK1 kinase activity (purified protein assayed with sphingosine and 32P-ATP). Core molecular function. |
| GO:0030100 regulation of endocytosis | IDA PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: SPHK1 recruitment is coupled to endocytosis. Non-core trafficking role. |
| GO:0031901 early endosome membrane | IDA PMID:24929359 Coupling between endocytosis and sphingosine kinase 1 recrui... | KEEP AS NON CORE | Summary: Direct localization to early endosome membranes. Non-core localization. |
| GO:0098793 presynapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS presynapse localization by similarity to mouse; corroborated by SynGO human annotations. Non-core. |
| GO:0030139 endocytic vesicle | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS endocytic-vesicle localization by similarity; consistent with human IDA endocytic evidence. Non-core. |
| GO:1905364 regulation of endosomal vesicle fusion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS by similarity to mouse; SPHK1 acts in later endosomal maturation/membrane fusion. Non-core trafficking role. |
| GO:0030100 regulation of endocytosis | IDA PMID:28049734 Sphingosine and Sphingosine Kinase 1 Involvement in Endocyti... | KEEP AS NON CORE | Summary: Sphingosine and SPHK1 drive endocytic membrane trafficking (dilated late endosomes, endophilin recruitment), partly independently of kinase activity. Non-core trafficking role. |
| GO:0034612 response to tumor necrosis factor | IDA PMID:23935096 Sphingosine kinase 1 regulates tumor necrosis factor-mediate... | KEEP AS NON CORE | Summary: SPHK1 functions in the TNF response (p38 MAPK-dependent suppression of RANTES). Downstream signaling context; non-core. |
| GO:1900745 positive regulation of p38MAPK cascade | IDA PMID:23935096 Sphingosine kinase 1 regulates tumor necrosis factor-mediate... | KEEP AS NON CORE | Summary: Loss of SPHK1 prevents TNF-induced p38 MAPK phosphorylation, so SPHK1 promotes the p38 cascade. Downstream signaling consequence; non-core. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS nuclear localization by similarity; also supported by human EXP evidence. Non-core. |
| GO:0006473 protein acetylation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: By similarity to mouse Sphk1: neuronal SphK1 acetylates COX2/PTGS2. A genuine moonlighting process supported By similarity in human; non-core. |
| GO:0016407 acetyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS serine acetyltransferase activity (COX2) by similarity to mouse Q8CI15. A secondary moonlighting activity; non-core in human. |
| GO:0032740 positive regulation of interleukin-17 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Downstream of S1P/TRAF2/NF-kappaB signaling; supported By similarity. Non-core inflammatory consequence. |
| GO:0050764 regulation of phagocytosis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: By similarity to mouse; microglial phagocytosis in the neuronal COX2/ neuroinflammation program. Non-core. |
| GO:0150077 regulation of neuroinflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: By similarity; neuroinflammation via neuronal COX2 acetylation. Non-core. |
| GO:1903978 regulation of microglial cell activation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: By similarity to mouse; part of the neuronal COX2/neuroinflammation program. Non-core. |
| GO:0038036 sphingosine-1-phosphate receptor activity | IMP PMID:23106337 Sphingosine 1-phosphate induces filopodia formation through ... | MARK AS OVER ANNOTATED | Summary: Incorrect molecular function. This paper shows that S1P (generated by SPHK1) acts through the receptor S1PR2 to activate ERM proteins and filopodia; SPHK1 supplies S1P endogenously and is not itself an S1P receptor. Assigning receptor activity to the kinase is a mis-annotation. Per policy this is an experimental (IMP) annotation, so it is not removed but flagged as an over-annotation/mis-assignment; the receptor activity belongs to S1PR2. |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:23106337 Sphingosine 1-phosphate induces filopodia formation through ... | MODIFY | Summary: SPHK1 is involved in endogenous S1P generation in this study, but the term names biosynthesis of the sphingosine base, which SPHK1 consumes. Replace with the more accurate sphingosine metabolic process. Proposed replacements: sphingosine metabolic process |
| GO:0046512 sphingosine biosynthetic process | IGI PMID:23106337 Sphingosine 1-phosphate induces filopodia formation through ... | MODIFY | Summary: IGI (with SPHK2, Q9NRA0) for the same S1P-generation phenotype. Same term concern: SPHK1 consumes sphingosine to make S1P. Replace with sphingosine metabolic process. Proposed replacements: sphingosine metabolic process |
| GO:0005515 protein binding | IPI PMID:19854831 Translocation of sphingosine kinase 1 to the plasma membrane... | MARK AS OVER ANNOTATED | Summary: IPI for interaction with CIB1 (Q99828), which mediates Ca2+-dependent plasma membrane translocation of SPHK1. Functionally important, but bare "protein binding" is uninformative; over-annotated. |
| GO:0005737 cytoplasm | IDA PMID:19854831 Translocation of sphingosine kinase 1 to the plasma membrane... | ACCEPT | Summary: Direct cytoplasmic localization (baseline before CIB1-mediated PM translocation). Consistent with core cytosolic compartment. |
| GO:0005886 plasma membrane | IDA PMID:19854831 Translocation of sphingosine kinase 1 to the plasma membrane... | ACCEPT | Summary: Direct demonstration of CIB1-mediated SPHK1 translocation to the plasma membrane. Core activation-dependent localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5218823 | ACCEPT | Summary: Reactome cytosol localization (PKC-phosphorylation module). Core resting compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5218845 | ACCEPT | Summary: Reactome cytosol localization. Core resting compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9836606 | ACCEPT | Summary: Reactome cytosol localization. Core resting compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9836621 | ACCEPT | Summary: Reactome cytosol localization. Core resting compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-391266 | ACCEPT | Summary: Reactome cytosol localization. Core resting compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-428273 | ACCEPT | Summary: Reactome cytosol localization (the SPHK1 phosphorylates sphingoid reaction). Core resting compartment. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9625814 | ACCEPT | Summary: Reactome cytosol localization. Core resting compartment. |
| GO:0005737 cytoplasm | IDA PMID:21075214 A critical role for the protein phosphatase 2A B'Ξ± regulator... | ACCEPT | Summary: Direct cytoplasmic localization (PP2A study). Consistent with core cytosolic compartment. |
| GO:0005886 plasma membrane | IDA PMID:21075214 A critical role for the protein phosphatase 2A B'Ξ± regulator... | ACCEPT | Summary: Direct plasma-membrane localization of endogenous SPHK1 modulated by PP2A B'alpha. Activation-dependent localization. |
| GO:0051721 protein phosphatase 2A binding | IPI PMID:21075214 A critical role for the protein phosphatase 2A B'Ξ± regulator... | KEEP AS NON CORE | Summary: Specific IPI: SPHK1 C-terminus binds the PP2A B'alpha (PPP2R5A) regulatory subunit, which targets PP2A to dephosphorylate SPHK1 at Ser225. Informative binding function (regulatory), retained but non-core relative to catalysis. |
| GO:0006670 sphingosine metabolic process | IDA PMID:20577214 Sphingosine-1-phosphate is a missing cofactor for the E3 ubi... | ACCEPT | Summary: Core metabolic process: SPHK1 phosphorylates sphingosine to S1P. This is the accurate process term for the enzyme's activity. |
| GO:0008481 sphingosine kinase activity | IDA PMID:20577214 Sphingosine-1-phosphate is a missing cofactor for the E3 ubi... | ACCEPT | Summary: IDA of SPHK1 kinase activity in the TRAF2/S1P study. Core molecular function. |
| GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway | IDA PMID:20577214 Sphingosine-1-phosphate is a missing cofactor for the E3 ubi... | KEEP AS NON CORE | Summary: SPHK1/S1P is required for TNF-induced NF-kappaB activation via TRAF2. Downstream signaling consequence; non-core. |
| GO:0031398 positive regulation of protein ubiquitination | IDA PMID:20577214 Sphingosine-1-phosphate is a missing cofactor for the E3 ubi... | KEEP AS NON CORE | Summary: S1P produced by SPHK1 stimulates TRAF2 E3 ligase activity, promoting Lys63 polyubiquitination of RIP1. Downstream consequence of the catalytic product; non-core. |
| GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction | IMP PMID:20577214 Sphingosine-1-phosphate is a missing cofactor for the E3 ubi... | KEEP AS NON CORE | Summary: SPHK1 promotes NF-kappaB activation in TNF signaling. Note the paper concerns the canonical (TNF/RIP1/IKK) NF-kappaB pathway; the specific "non-canonical" qualifier may be an imprecise term choice, but the essential NF-kappaB role is supported. Downstream signaling consequence; non-core. |
| GO:0048146 positive regulation of fibroblast proliferation | IDA PMID:15623571 Phosphorylation-dependent translocation of sphingosine kinas... | KEEP AS NON CORE | Summary: Overexpression of SPHK1 (phosphorylation/PM-translocation dependent) enhances fibroblast (NIH3T3) proliferation. Downstream proliferative consequence of S1P; non-core. |
| GO:0005737 cytoplasm | IDA PMID:15623571 Phosphorylation-dependent translocation of sphingosine kinas... | ACCEPT | Summary: Wild-type SPHK1 is mainly cytoplasmic; PM-targeting drives oncogenic signaling. Core resting compartment. |
| GO:0008481 sphingosine kinase activity | IDA PMID:15623571 Phosphorylation-dependent translocation of sphingosine kinas... | ACCEPT | Summary: IDA of SPHK1 (SK) activity in transfected cells. Core molecular function. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:15623571 Phosphorylation-dependent translocation of sphingosine kinas... | KEEP AS NON CORE | Summary: SPHK1 (PM-translocated) protects cells from serum-deprivation apoptosis. Downstream pro-survival consequence; non-core. |
| GO:0000287 magnesium ion binding | IDA PMID:10947957 Human sphingosine kinase: purification, molecular cloning an... | KEEP AS NON CORE | Summary: Mg2+ is the required cofactor for the kinase reaction (UniProt COFACTOR Mg(2+)). Genuine catalytic cofactor binding; supporting the core activity but non-core as a standalone function. |
| GO:0005516 calmodulin binding | IDA PMID:10947957 Human sphingosine kinase: purification, molecular cloning an... | ACCEPT | Summary: SPHK1 binds calmodulin; the calmodulin-binding site overlaps the CIB1 site that regulates Ca2+-dependent membrane translocation. Informative regulatory binding function. Core-adjacent regulatory function. |
| GO:0005524 ATP binding | IDA PMID:12393916 The nucleotide-binding site of human sphingosine kinase 1. | ACCEPT | Summary: Direct mapping of the nucleotide (ATP)-binding site of human SPHK1 (FSBA affinity labeling, Gly82 mutagenesis). Core molecular function (substrate/cofactor binding for the kinase reaction). |
| GO:0005829 cytosol | TAS PMID:10863092 Human sphingosine kinase: molecular cloning, functional char... | ACCEPT | Summary: Cytosolic localization of human SPHK1 (cloning/characterization paper). Core resting compartment. |
| GO:0008481 sphingosine kinase activity | IDA PMID:10863092 Human sphingosine kinase: molecular cloning, functional char... | ACCEPT | Summary: Direct demonstration of human SPHK1 sphingosine kinase activity and substrate specificity. Core molecular function. |
| GO:0019722 calcium-mediated signaling | IDA PMID:10947957 Human sphingosine kinase: purification, molecular cloning an... | KEEP AS NON CORE | Summary: SPHK1 activity/localization is calcium-regulated (calmodulin/CIB1). This annotation is at the edge of the enzyme's regulatory context rather than a core signaling role. Retain as non-core. |
| GO:0030307 positive regulation of cell growth | IDA PMID:12441135 Sphingosine kinase type 1 promotes estrogen-dependent tumori... | KEEP AS NON CORE | Summary: SPHK1 overexpression confers a growth advantage in MCF-7 breast cancer cells. Downstream proliferative consequence of S1P; non-core. |
| GO:0030335 positive regulation of cell migration | IDA PMID:12441135 Sphingosine kinase type 1 promotes estrogen-dependent tumori... | KEEP AS NON CORE | Summary: S1P produced by SPHK1 promotes cell migration/invasion. Downstream consequence; non-core. |
| GO:0035556 intracellular signal transduction | TAS PMID:10947957 Human sphingosine kinase: purification, molecular cloning an... | MARK AS OVER ANNOTATED | Summary: Generic signaling term; SPHK1 acts in intracellular S1P signaling but this is uninformative relative to the specific downstream terms. |
| GO:0043066 negative regulation of apoptotic process | TAS PMID:10947957 Human sphingosine kinase: purification, molecular cloning an... | KEEP AS NON CORE | Summary: Anti-apoptotic role via S1P (TAS). Downstream consequence; non-core. |
| GO:0045766 positive regulation of angiogenesis | IDA PMID:12441135 Sphingosine kinase type 1 promotes estrogen-dependent tumori... | KEEP AS NON CORE | Summary: SPHK1-overexpressing tumors show higher microvessel density; S1P is pro-angiogenic. Downstream physiological consequence; non-core. |
| GO:0045931 positive regulation of mitotic cell cycle | IDA PMID:12441135 Sphingosine kinase type 1 promotes estrogen-dependent tumori... | KEEP AS NON CORE | Summary: SPHK1 promotes proliferation of MCF-7 cells. Downstream consequence; non-core. |
| GO:0045987 positive regulation of smooth muscle contraction | IDA PMID:12847068 Sphingosine kinase modulates microvascular tone and myogenic... | KEEP AS NON CORE | Summary: SPHK1 modulates microvascular tone/myogenic responses via RhoA/Rho kinase in smooth muscle. Tissue-level downstream consequence of S1P; non-core. |
| GO:0046521 sphingoid catabolic process | NAS PMID:10863092 Human sphingosine kinase: molecular cloning, functional char... | MARK AS OVER ANNOTATED | Summary: NAS assertion of a sphingoid catabolic role. SPHK1 phosphorylates sphingosine (a metabolic step feeding both signaling and, via S1P lyase, sphingoid degradation), but "catabolic process" is a debatable/imprecise framing and is only NAS. Treat as over-annotation relative to sphingosine metabolic process. |
| GO:0003677 DNA binding | IDA PMID:12393916 The nucleotide-binding site of human sphingosine kinase 1. | UNDECIDED | Summary: Almost certainly a curation error. PMID:12393916 characterizes the ATP (nucleotide)-binding site of SPHK1 via FSBA affinity labeling and mutagenesis; it does not demonstrate DNA binding, and there is no biological basis for SPHK1 (a cytosolic lipid kinase) binding DNA. This appears to be a nucleotide-binding -> DNA-binding slip. As an experimental annotation it is not removed per policy, but it is flagged; UNDECIDED pending curator verification of the original assertion. |
| GO:0005516 calmodulin binding | IDA PMID:12393916 The nucleotide-binding site of human sphingosine kinase 1. | ACCEPT | Summary: Calmodulin binding of human SPHK1 (also independently supported by PMID:10947957). Informative regulatory binding function. |
| GO:0008481 sphingosine kinase activity | IDA PMID:12393916 The nucleotide-binding site of human sphingosine kinase 1. | ACCEPT | Summary: IDA of SPHK1 kinase activity (nucleotide-binding-site study). Core molecular function. |
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Download this section (compressed HTML)Q: Is the MGI "DNA binding" (GO:0003677) annotation citing PMID:12393916 a curation error for nucleotide/ATP binding, and should it be corrected or removed?
Q: Should SPHK1's process annotations use sphingosine metabolic process / S1P biosynthesis rather than "sphingosine biosynthetic process" (which describes synthesis of the sphingosine base that SPHK1 consumes)?
Q: How much of SPHK1's endocytic-trafficking role is genuinely independent of its kinase activity versus dependent on local S1P production?
Experiment: Use separation-of-function mutants (catalytically dead D81A/G82D vs membrane-binding-deficient L194Q/FL197-198AQ) to dissect kinase-dependent signaling from kinase-independent membrane/endocytic roles.
Experiment: Perform lipidomic quantification of S1P, sphingosine and ceramide upon SPHK1 knockout/rescue to define its quantitative contribution to the sphingolipid rheostat versus SPHK2.
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