SPHK2 (sphingosine kinase 2) is a diacylglycerol-kinase-like lipid kinase (DAGKc domain) that phosphorylates sphingoid bases, principally sphingosine and dihydrosphingosine (sphinganine), using ATP to produce the bioactive lipid mediator sphingosine-1-phosphate (S1P) and dihydro-S1P (EC 2.7.1.91). It is one of two mammalian sphingosine kinases; unlike the largely cytosolic, pro-survival SPHK1, SPHK2 is a multi-compartment enzyme found in the nucleus, cytoplasm, endoplasmic reticulum and mitochondrial inner membrane, with a nuclear localization signal and a protein-kinase-D-regulated nuclear export signal that govern nucleocytoplasmic shuttling. Nuclear S1P generated by SPHK2 binds to and inhibits the histone deacetylases HDAC1 and HDAC2 within co-repressor complexes, raising histone acetylation (H3-K9, H4-K5, H2B-K12) and thereby coupling nuclear sphingolipid metabolism to epigenetic regulation of gene transcription. In mitochondria, S1P produced by SPHK2 binds prohibitin 2 to support cytochrome-c oxidase (complex IV) assembly and respiration. In contrast to SPHK1, SPHK2 tends to raise intracellular ceramide and can be pro-apoptotic (it contains a putative BH3 motif) and inhibits DNA synthesis when nuclear. SPHK2 activity is enhanced by ERK/MAPK phosphorylation and by interaction with elongation factor eEF1A1, and the enzyme also phosphorylates the immunomodulatory prodrug FTY720 (fingolimod).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0008481 sphingosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core molecular function. Phylogenetic (IBA) inference of the defining sphingosine kinase activity, well supported by direct human experiments (PMID:10751414, PMID:12954646, PMID:19729656) and the UniProt catalytic-activity record. |
| GO:0006669 sphinganine-1-phosphate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Direct biological process of the enzyme: SPHK2 phosphorylates sphinganine (dihydrosphingosine) to sphinganine-1-phosphate (dihydro-S1P). Supported by IDA annotations from PMID:10751414 and PMID:19729656. |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Real but context-dependent, downstream consequence. Unlike pro-survival SPHK1, SPHK2 (putative BH3-only protein) enhances apoptosis in some settings. A valid biological role but not the core enzymatic function. |
| GO:0046512 sphingosine biosynthetic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assignment to sphingosine biosynthesis. Note SPHK2 consumes sphingosine (phosphorylating it to S1P) rather than synthesizing it; this reflects the family-level involvement in sphingoid-base/sphingolipid metabolism. Kept as non-core given the imprecise direction relative to SPHK2's actual reaction. |
| GO:0003376 sphingosine-1-phosphate receptor signaling pathway | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inter-ontology inference derived from the erroneous 'S1P receptor activity' MF annotation. SPHK2 produces the S1P ligand but is not itself a receptor and does not transduce the receptor signaling pathway; this propagated term is an over-annotation. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Nuclear localization is well established experimentally (PMID:12954646, PMID:19729656). This automated electronic annotation is redundant with the EXP/IDA annotations. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Cytoplasmic localization is supported experimentally (PMID:12954646, PMID:17635916, PMID:29615132). This electronic annotation is redundant with the EXP/IDA annotations. |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Mitochondrial inner-membrane localization, transferred from mouse ortholog Q9JIA7. Consistent with mitochondrial S1P production (PMID:20959514). Redundant with the ISS annotation to the same term. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Subcellular-location keyword mapping derived from an isoform-2 lysosomal-membrane proteomics survey (PMID:17897319). A minor, isoform-specific co-purification rather than a core localization. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: ER localization (ISS from mouse Q9JIA7; SPHK2 accumulates in the ER on serum starvation, PMID:16118219). This electronic row repeats the ISS claim through the combined Ensembl ortholog (Q9JIA7) and UniProt keyword (SL-0095) pipeline. Reason: ORGANELLES check (2026-11-06). The source is mouse Sphk2 (Q9JIA7), whose ER location is a UniProt IDA from PMID:16118219 (abstract only in cache); the human UniProt ER line is ECO:0000250 by similarity to that entry. The abstract reports that serum starvation increased the proportion of SphK2 in the ER, in a study built on overexpressed SphK2, and that knockdown of endogenous SphK2 reduced recycling of sphingosine into ceramide, a pathway whose ceramide synthases are ER enzymes. SPHK2 is a soluble kinase with no signal peptide or transmembrane segment; its N-terminal region binds sulfatide and phosphoinositides and is required for membrane localization (PMID:19168031). So this is a stimulus-regulated, recruited cytosolic pool on the ER surface, not a resident or transit pool, and it stays at the root with no ER membrane or lumen row. KEEP_AS_NON_CORE rather than MARK_AS_OVER_ANNOTATED is a close call - the only location assay is on an overexpressed construct, but the shift is physiologically regulated and fits the knockdown effect on ceramide recycling. Seeing endogenous SPHK2 in a marker-controlled ER fraction after serum starvation would settle it. Supporting Evidence: PMID:16118219 Serum starvation increased the proportion of SphK2 in the endoplasmic reticulum |
| GO:0008481 sphingosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function, electronically inferred (ARBA/RHEA/EC mapping). Redundant with the strong IDA/EXP evidence. |
| GO:0016301 kinase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro2GO mapping to the generic parent '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 to a broad regulatory term. SPHK2 participates in lipid (sphingolipid) metabolism; this generic 'regulation of lipid metabolic process' is an imprecise over-annotation relative to the specific sphingolipid 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. SPHK2 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. SPHK2 is a 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:0042981 regulation of apoptotic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Broad ARBA electronic term. SPHK2 modulates apoptosis (usually positively); the more specific 'positive regulation of apoptotic process' captures this better. |
| GO:0046512 sphingosine biosynthetic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic duplicate of the IBA/IMP sphingosine biosynthesis annotations. As noted above, SPHK2 phosphorylates (consumes) sphingosine; kept only as non-core family-level metabolism. |
| GO:0051049 regulation of transport | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Very broad ARBA electronic annotation with no specific experimental support for SPHK2 regulating transport. Over-annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI capturing the SPHK2-OPTN (Q96CV9) interaction from a neurodegeneration interactome Y2H screen (also listed in UniProt INTERACTION). Bare 'protein binding' is uninformative about function; retained but flagged as over-annotation per policy. |
| GO:0002720 positive regulation of cytokine production involved in immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara transfer of a mast-cell immune role from mouse Sphk2 (Q9JIA7). Legitimate ortholog-based function but a tissue-specific downstream consequence; duplicated by an ISS annotation to the same term. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mitochondrial localization (Ensembl transfer from mouse), consistent with mitochondrial S1P/PHB2 function (PMID:20959514). Redundant with the ISS annotation. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cytosolic localization (Ensembl transfer), also supported by IDA (PMID:10751414) and Reactome TAS. Redundant electronic annotation. |
| GO:0006669 sphinganine-1-phosphate biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl electronic duplicate of the direct sphinganine-1-phosphate biosynthesis role. Redundant with the IDA/IBA annotations. |
| GO:0006670 sphingosine metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Sphingosine metabolism (Ensembl transfer from mouse). SPHK2 acts on sphingosine, so this is correct at the metabolic-process level though less specific than the S1P biosynthesis terms. Duplicated by an ISS annotation. |
| GO:0007565 female pregnancy | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Distal, whole-organism physiology transferred from a rat ortholog (A6JB73) by Ensembl Compara. No direct evidence for a human SPHK2 role in pregnancy; an over-annotation. |
| GO:0016020 membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic 'membrane' localization (Ensembl transfer), also supported by IDA (PMID:10751414). Uninformative and redundant with more specific compartment terms. |
| GO:0030308 negative regulation of cell growth | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of the anti-proliferative role of nuclear SPHK2 (inhibits DNA synthesis, G1/S arrest; PMID:12954646). A genuine downstream consequence; duplicated by an ISS annotation. |
| GO:0032736 positive regulation of interleukin-13 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mast-cell cytokine role transferred from mouse Sphk2 (Ensembl). Tissue-specific downstream consequence; duplicated by an ISS annotation. |
| GO:0032755 positive regulation of interleukin-6 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mast-cell IL-6 role transferred from mouse Sphk2 (Ensembl). Tissue-specific downstream consequence; duplicated by an ISS annotation. |
| GO:0032760 positive regulation of tumor necrosis factor production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mast-cell TNF role transferred from mouse Sphk2 (Ensembl). Tissue-specific downstream consequence; duplicated by an ISS annotation. |
| GO:0033008 positive regulation of mast cell activation involved in immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mast-cell activation role transferred from mouse Sphk2 (Ensembl). Tissue-specific downstream consequence; duplicated by an ISS annotation. |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: S1P produced by SPHK2 acts intracellularly (HDAC inhibition, PHB2 binding). Correct but very generic; duplicated by an ISS annotation. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl electronic duplicate of the IDA/IBA pro-apoptotic role (PMID:16118219). Downstream consequence; redundant. |
| GO:0043122 regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NF-kB regulation transferred from mouse Sphk2 (Ensembl), consistent with SphK-TRAF2/ mast-cell signaling. Downstream/context-specific consequence; duplicated by an ISS annotation. |
| GO:0043306 positive regulation of mast cell degranulation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mast-cell degranulation role transferred from mouse Sphk2 (Ensembl). Tissue-specific downstream consequence; duplicated by an ISS annotation. |
| GO:1903426 regulation of reactive oxygen species biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ROS-regulation role transferred from mouse Sphk2 (Ensembl), linked to mitochondrial function in dopaminergic neurons (By similarity). Downstream consequence; duplicated by an ISS annotation. |
| GO:2000304 positive regulation of ceramide biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl electronic duplicate of the IDA ceramide-biosynthesis role (PMID:16118219, SPHK2 raises C16-ceramide). Downstream consequence; redundant. |
| GO:2001169 regulation of ATP biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ATP-biosynthesis regulation transferred from mouse Sphk2 (Ensembl), linked to mitochondrial respiration (PMID:20959514). Downstream consequence; duplicated by an ISS annotation. |
| GO:0030148 sphingolipid biosynthetic process | TAS Reactome:R-HSA-1660661 | KEEP AS NON CORE | Summary: Reactome pathway assignment (sphingolipid de novo biosynthesis). Correct pathway context; broader than the specific S1P-biosynthesis role but a reasonable non-core process annotation. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence localization to the nucleoplasm. Consistent with SPHK2's nuclear localization, although PMID:19729656 reports endogenous SPHK2 mainly on chromatin rather than free nucleoplasm. Kept as a valid, non-core localization observation. |
| GO:0005634 nucleus | EXP PMID:12954646 Sphingosine kinase 2 is a nuclear protein and inhibits DNA s... | ACCEPT | Summary: Direct experimental demonstration that SPHK2 localizes to the nucleus (functional NLS mapped). Core localization for the nuclear moonlighting function. |
| GO:0005634 nucleus | EXP PMID:16103110 Involvement of N-terminal-extended form of sphingosine kinas... | ACCEPT | Summary: Experimental nuclear localization (serum-dependent nuclear translocation of the N-terminal-extended SPHK2-L form). Corroborates the nuclear localization. |
| GO:0005634 nucleus | EXP PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | ACCEPT | Summary: Experimental nuclear/chromatin localization underpinning the nuclear S1P-HDAC mechanism. Core localization. |
| GO:0005634 nucleus | EXP PMID:20197547 Cleavage of sphingosine kinase 2 by caspase-1 provokes its r... | ACCEPT | Summary: Experimental nuclear localization in the caspase-1 cleavage study. Redundant with the other EXP nucleus annotations but valid. |
| GO:0005737 cytoplasm | EXP PMID:12954646 Sphingosine kinase 2 is a nuclear protein and inhibits DNA s... | KEEP AS NON CORE | Summary: Direct experimental cytosolic/cytoplasmic localization (SPHK2 in nucleus and cytosol). Valid non-core localization. |
| GO:0005737 cytoplasm | EXP PMID:16103110 Involvement of N-terminal-extended form of sphingosine kinas... | KEEP AS NON CORE | Summary: Experimental cytoplasmic localization (serum-dependent nucleocytoplasmic distribution). Valid non-core localization. |
| GO:0005737 cytoplasm | EXP PMID:20197547 Cleavage of sphingosine kinase 2 by caspase-1 provokes its r... | KEEP AS NON CORE | Summary: Experimental cytoplasmic localization in the caspase-1 cleavage study. Valid non-core localization. |
| GO:0005743 mitochondrial inner membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrial inner-membrane localization inferred by sequence similarity to mouse Sphk2, consistent with mitochondrial S1P production (PMID:20959514). Non-core localization. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ER localization inferred by similarity to mouse Sphk2; SPHK2 accumulates in the ER on serum starvation (PMID:16118219). Non-core localization. Reason: ORGANELLES check (2026-11-06). The source is mouse Sphk2 (Q9JIA7), whose ER location is a UniProt IDA from PMID:16118219 (abstract only in cache); the human UniProt ER line is ECO:0000250 by similarity to that entry. The abstract reports that serum starvation increased the proportion of SphK2 in the ER, in a study built on overexpressed SphK2, and that knockdown of endogenous SphK2 reduced recycling of sphingosine into ceramide, a pathway whose ceramide synthases are ER enzymes. SPHK2 is a soluble kinase with no signal peptide or transmembrane segment; its N-terminal region binds sulfatide and phosphoinositides and is required for membrane localization (PMID:19168031). So this is a stimulus-regulated, recruited cytosolic pool on the ER surface, not a resident or transit pool, and it stays at the root with no ER membrane or lumen row. KEEP_AS_NON_CORE rather than MARK_AS_OVER_ANNOTATED is a close call - the only location assay is on an overexpressed construct, but the shift is physiologically regulated and fits the knockdown effect on ceramide recycling. Seeing endogenous SPHK2 in a marker-controlled ER fraction after serum starvation would settle it. GOA carries this ISS row twice (2019 and 2024 dates, same Q9JIA7 source); both are covered by this review. Supporting Evidence: PMID:16118219 Serum starvation increased the proportion of SphK2 in the endoplasmic reticulum file:human/SPHK2/SPHK2-uniprot.txt Required for binding to sulfatide and phosphoinositides and for membrane localizatione |
| GO:0008481 sphingosine kinase activity | EXP PMID:12954646 Sphingosine kinase 2 is a nuclear protein and inhibits DNA s... | ACCEPT | Summary: Direct experimental sphingosine kinase activity. Core molecular function. |
| GO:0035556 intracellular signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Generic intracellular signaling role inferred by similarity to mouse Sphk2. Correct but non-specific; non-core. Duplicated by an Ensembl IEA. |
| GO:0001727 lipid kinase activity | TAS Reactome:R-HSA-9695949 | MARK AS OVER ANNOTATED | Summary: Reactome TAS to the parent 'lipid kinase activity'. Correct but less informative than the specific sphingosine kinase activity term. |
| GO:0042393 histone binding | IDA PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | ACCEPT | Summary: Directly demonstrated: SPHK2 (but not SPHK1) binds histone H3 specifically (and not H4/H2B/H2A). Supporting molecular function for the nuclear chromatin/HDAC-inhibition role. |
| GO:0005634 nucleus | IDA Q9NRA0-1 PMID:16103110 Involvement of N-terminal-extended form of sphingosine kinas... | ACCEPT | Summary: Isoform-1 (SK2-L) nuclear localization by IDA, tested on the N-terminal-extended form. Core localization; consistent with the EXP nucleus annotations. |
| GO:0005737 cytoplasm | IDA Q9NRA0-1 PMID:16103110 Involvement of N-terminal-extended form of sphingosine kinas... | KEEP AS NON CORE | Summary: Isoform-1 cytoplasmic localization by IDA. Valid non-core localization. |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mitochondrial localization inferred by similarity to mouse Sphk2; consistent with the mitochondrial S1P/PHB2 function (PMID:20959514). Non-core localization. |
| GO:1903426 regulation of reactive oxygen species biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ROS-regulation role inferred by similarity to mouse Sphk2 (mitochondrial function in dopaminergic neurons, By similarity). Downstream consequence; non-core. |
| GO:2001169 regulation of ATP biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ATP-biosynthesis regulation inferred by similarity to mouse Sphk2, linked to mitochondrial respiration (PMID:20959514). Downstream consequence; non-core. |
| GO:0002720 positive regulation of cytokine production involved in immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mast-cell cytokine role inferred by similarity to mouse Sphk2. Tissue-specific downstream consequence; non-core. |
| GO:0005515 protein binding | IPI PMID:18263879 Eukaryotic elongation factor 1A interacts with sphingosine k... | MARK AS OVER ANNOTATED | Summary: IPI for the SPHK2-eEF1A1 (P68104) interaction, which directly enhances SPHK2 catalytic activity ~2.6-fold. A real, functionally relevant interaction, but bare 'protein binding' is uninformative; flagged as over-annotation per policy (a more specific 'enzyme activator' MF could be considered). |
| GO:0006670 sphingosine metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sphingosine metabolism inferred by similarity to mouse Sphk2. SPHK2 acts on sphingosine, so correct at the metabolic-process level. Non-core; duplicated by an Ensembl IEA. |
| GO:0032736 positive regulation of interleukin-13 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mast-cell IL-13 role inferred by similarity to mouse Sphk2. Tissue-specific downstream consequence; non-core. |
| GO:0032755 positive regulation of interleukin-6 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mast-cell IL-6 role inferred by similarity to mouse Sphk2. Tissue-specific downstream consequence; non-core. |
| GO:0032760 positive regulation of tumor necrosis factor production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mast-cell TNF role inferred by similarity to mouse Sphk2. Tissue-specific downstream consequence; non-core. |
| GO:0033008 positive regulation of mast cell activation involved in immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mast-cell activation role inferred by similarity to mouse Sphk2. Tissue-specific downstream consequence; non-core. |
| GO:0043122 regulation of canonical NF-kappaB signal transduction | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: NF-kB regulation inferred by similarity to mouse Sphk2. Downstream/context-specific consequence; non-core. |
| GO:0043306 positive regulation of mast cell degranulation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mast-cell degranulation role inferred by similarity to mouse Sphk2. Tissue-specific downstream consequence; non-core. |
| GO:0005634 nucleus | IDA PMID:17635916 Protein kinase D-mediated phosphorylation and nuclear export... | ACCEPT | Summary: Direct nuclear localization; PKD phosphorylation of the NES drives nuclear export. Core localization. |
| GO:0005737 cytoplasm | IDA PMID:17635916 Protein kinase D-mediated phosphorylation and nuclear export... | KEEP AS NON CORE | Summary: Direct cytoplasmic localization after PKD-mediated nuclear export. Valid non-core localization. |
| GO:1904628 cellular response to phorbol 13-acetate 12-myristate | IDA PMID:17635916 Protein kinase D-mediated phosphorylation and nuclear export... | KEEP AS NON CORE | Summary: PMA induces PKD-dependent SPHK2 phosphorylation and nuclear export. A specific, directly demonstrated cellular response, but a regulatory/context response rather than a core function. |
| GO:0006669 sphinganine-1-phosphate biosynthetic process | IDA PMID:10751414 Molecular cloning and functional characterization of a novel... | ACCEPT | Summary: Direct evidence that SPHK2 phosphorylates dihydrosphingosine (a better substrate than sphingosine) to dihydro-S1P; SPHK2 expression elevates SPP. Core biological process. |
| GO:0008481 sphingosine kinase activity | IDA PMID:10751414 Molecular cloning and functional characterization of a novel... | ACCEPT | Summary: Original cloning and functional characterization directly demonstrating sphingosine kinase activity. Core molecular function. |
| GO:0000786 nucleosome | IDA PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | ACCEPT | Summary: SPHK2 is present in purified mononucleosomes and associates with core histones on chromatin. Supports the chromatin-associated nuclear function. |
| GO:0005515 protein binding | IPI PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | MARK AS OVER ANNOTATED | Summary: IPI capturing SPHK2 interactions with HDAC1/HDAC2/MBD2/SIN3A co-repressor components (and histone H3). Functionally central to the nuclear HDAC-inhibition mechanism, but bare 'protein binding' is uninformative; the specific histone-binding (GO:0042393) function captures this better. The HDAC1/2 inhibition itself is executed by the diffusible product S1P, not by the SPHK2 polypeptide, so it is not a molecular function of the protein. |
| GO:0006669 sphinganine-1-phosphate biosynthetic process | IDA PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | ACCEPT | Summary: Direct evidence that SPHK2 produces S1P and dihydro-S1P in the nucleus. Core biological process. |
| GO:0008481 sphingosine kinase activity | IDA PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | ACCEPT | Summary: Direct demonstration of nuclear SPHK2 sphingosine kinase activity (S1P production); catalytically-dead G212E mutant abolishes it. Core molecular function. |
| GO:0045815 transcription initiation-coupled chromatin remodeling | IDA PMID:19729656 Regulation of histone acetylation in the nucleus by sphingos... | KEEP AS NON CORE | Summary: SPHK2/nuclear-S1P enhances histone H3 acetylation at the p21 and c-fos promoters and increases their transcription. Directly supported; the biological-process consequence of the nuclear-S1P/HDAC-inhibition mechanism (kept as non-core). The HDAC1/2 inhibition is executed by the diffusible product S1P, not by the SPHK2 polypeptide, so it is not a molecular function of the protein; SPHK2's contribution is captured by the sphingosine kinase activity and histone binding (GO:0042393). |
| GO:1904959 regulation of cytochrome-c oxidase activity | IMP PMID:20959514 Sphingosine-1-phosphate produced by sphingosine kinase 2 in ... | KEEP AS NON CORE | Summary: Mitochondrial S1P produced by SPHK2 binds PHB2 to support complex IV assembly; SphK2 depletion causes cytochrome-c oxidase dysfunction. Directly supported downstream consequence of mitochondrial S1P production. |
| GO:0030308 negative regulation of cell growth | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Anti-proliferative role inferred by similarity to mouse Sphk2 and supported by human data (nuclear SPHK2 inhibits DNA synthesis, PMID:12954646). Downstream consequence; non-core. |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:16118219 SphK1 and SphK2, sphingosine kinase isoenzymes with opposing... | KEEP AS NON CORE | Summary: Directly supported: SPHK2 (putative BH3-only protein) enhances apoptosis, opposite to SPHK1. A real biological role but a downstream, context-dependent consequence rather than the core enzymatic function. |
| GO:2000304 positive regulation of ceramide biosynthetic process | IDA PMID:16118219 SphK1 and SphK2, sphingosine kinase isoenzymes with opposing... | KEEP AS NON CORE | Summary: Directly supported: SPHK2 overexpression increases C16-ceramide (opposite to SPHK1), shifting the sphingolipid balance. Downstream metabolic consequence; non-core. |
| GO:0005634 nucleus | IDA PMID:29615132 Neuronal sphingosine kinase 2 subcellular localization is al... | ACCEPT | Summary: Immunohistochemical/immunofluorescence nuclear localization of neuronal SPHK2 in human brain (enriched in AD). Corroborates nuclear localization. |
| GO:0005737 cytoplasm | IDA PMID:29615132 Neuronal sphingosine kinase 2 subcellular localization is al... | KEEP AS NON CORE | Summary: Cytoplasmic localization of neuronal SPHK2 in human brain (decreases with amyloid density). Valid non-core localization. |
| GO:0038036 sphingosine-1-phosphate receptor activity | IMP PMID:23106337 Sphingosine 1-phosphate induces filopodia formation through ... | MARK AS OVER ANNOTATED | Summary: Molecularly incorrect assignment. GO:0038036 is a GPCR that binds S1P and signals through a G-protein; SPHK2 is the kinase producing S1P. PMID:23106337 studies S1P acting on the receptor S1PR2 to drive ERM phosphorylation/filopodia and states the relevant S1P is generated 'predominantly by the action of SK1'; SPHK2 was knocked down as one of the kinase controls. This conflates the kinase with the receptor. Retained (experimental) but flagged as over-annotation; the MF is not SPHK2's. |
| GO:0046512 sphingosine biosynthetic process | IMP PMID:23106337 Sphingosine 1-phosphate induces filopodia formation through ... | MARK AS OVER ANNOTATED | Summary: From an S1P/S1PR2 signaling paper in which SPHK2 was knocked down as a control; the study attributes the S1P generation predominantly to SPHK1. 'Sphingosine biosynthetic process' is also not SPHK2's actual reaction (SPHK2 consumes sphingosine). Weakly supported here; retained as an over-annotation rather than a core process. |
| GO:0046512 sphingosine biosynthetic process | IGI PMID:23106337 Sphingosine 1-phosphate induces filopodia formation through ... | MARK AS OVER ANNOTATED | Summary: Genetic-interaction annotation (with SPHK1, UniProtKB:Q9NYA1) from the same S1P/S1PR2 signaling paper where SPHK2 was a knockdown control and S1P generation is attributed mainly to SPHK1. As above, sphingosine biosynthesis is not SPHK2's reaction; retained as an over-annotation. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: High-throughput proteomic co-purification of isoform 2 with placental lysosomal membranes. A minor, isoform-specific association rather than a core localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9695917 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (SPHK2-inhibitor-binding reaction context). Consistent with cytosolic localization; non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9695949 | KEEP AS NON CORE | Summary: Reactome cytosolic localization (SPHK2 phosphorylates sphingoid reaction context). Consistent with cytosolic localization; non-core. |
| GO:0005829 cytosol | IDA PMID:10751414 Molecular cloning and functional characterization of a novel... | KEEP AS NON CORE | Summary: Direct cytosolic localization from the original characterization. Valid non-core localization. |
| GO:0016020 membrane | IDA PMID:10751414 Molecular cloning and functional characterization of a novel... | MARK AS OVER ANNOTATED | Summary: Generic 'membrane' localization from the original characterization; SPHK2 also associates with membranes via its N-terminal lipid-binding region. Uninformative relative to specific compartment terms. |
| GO:0005515 protein binding | IPI PMID:11777919 Sphingosine kinase interacts with TRAF2 and dissects tumor n... | MARK AS OVER ANNOTATED | Summary: IPI for a SphK-TRAF2 (Q12933) interaction. The paper describes 'sphingosine kinase (SphK)' generically in a TNF/TRAF2/NF-kB context (largely SPHK1); the attribution to SPHK2 is uncertain and 'protein binding' is uninformative. Retained (IPI) but flagged as over-annotation per policy. |
| GO:0031267 small GTPase binding | NAS PMID:12391145 Sphingosine kinase mediates vascular endothelial growth fact... | MARK AS OVER ANNOTATED | Summary: NAS (author-statement) annotation from a VEGF/Ras/MAPK signaling paper that explicitly shows siRNA targeting SPK1, but NOT SPK2, blocks VEGF-induced Ras-GTP accumulation. There is no direct assay of SPHK2 binding a small GTPase; the effect is attributed to SPHK1. Not experimental and not supported for SPHK2; over-annotation. |
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