Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Functional characterization of human sphingosine kinase-1.
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Human SPHK1 specifically phosphorylates D-erythro-sphingosine and, to a lesser extent, sphinganine, but not diacylglycerol, ceramide or phosphatidylinositol, establishing its substrate specificity as a sphingosine kinase.
"hSPHK1 also specifically phosphorylated D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N, N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol."
Human sphingosine kinase: molecular cloning, functional characterization and tissue distribution.
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Cloning and functional characterization of human SPHK1; product S1P is a signaling molecule with intra- and extracellular functions.
"Sphingosine-1-phosphate (SPP), the product of sphingosine kinase, is an important signaling molecule with intra- and extracellular functions."
Human sphingosine kinase: purification, molecular cloning and characterization of the native and recombinant enzymes.
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Human SPHK1 purified from placenta binds calmodulin (calmodulin-affinity chromatography step) and requires Mg2+; kinetics characterized.
"calmodulin-affinity chromatography and gel-filtration chromatography"
1-O-Hexadecyl-2-desoxy-2-amino-sn-glycerol, a substrate for human sphingosine kinase.
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Only the D-erythro isomer of the sphingoid bases is efficiently phosphorylated by human sphingosine kinase, confirming stereospecific substrate recognition.
"Only the D-erythro isomer of the sphingoid bases, sphinganine and sphingenine, was effectively phosphorylated."
Cloning and characterization of a protein kinase A anchoring protein (AKAP)-related protein that interacts with and regulates sphingosine kinase 1 activity.
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SPHK1 interacts with SPHKAP/SKIP, which reduces SPHK1 activity and its biological functions.
"SKIP overexpression in NIH 3T3 fibroblasts reduced SPHK1 activity and interfered with its biological functions."
The nucleotide-binding site of human sphingosine kinase 1.
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Elucidation of the ATP (nucleotide)-binding site of human SPHK1; Gly82 is important for ATP binding.
"Here we have elucidated the nucleotide-binding site of human sphingosine kinase 1 (hSK1) through a combination of site-directed mutagenesis and affinity labeling with the ATP analogue, FSBA."
Sphingosine kinase type 1 promotes estrogen-dependent tumorigenesis of breast cancer MCF-7 cells.
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SPHK1 overexpression raises S1P, blocks apoptosis, confers estrogen-dependent growth advantage and larger, more vascularized tumors in MCF-7 breast cancer.
"Enforced expression of sphingosine kinase type 1 (SPHK1) increased S1P levels and blocked MCF-7 cell death induced by anti-cancer drugs, sphingosine, and TNF-alpha."
Sphingosine kinase modulates microvascular tone and myogenic responses through activation of RhoA/Rho kinase.
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Sphk1 overexpression increases resting tone and myogenic responses of resistance arteries via RhoA/Rho kinase in smooth muscle.
"resting tone and myogenic responses of isolated resistance arteries increased with forced expression of Sphk1 in smooth muscle cells of these arteries"
Identification of functional nuclear export sequences in human sphingosine kinase 1.
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Human SPHK1 is predominantly cytoplasmic and shuttles between cytoplasm and nucleus via two functional NES (CRM1-dependent export).
"Human SPHK1 (hSPHK1) was localized predominantly in the cytoplasm when transiently expressed in Cos7 cells."
Phosphorylation-dependent translocation of sphingosine kinase to the plasma membrane drives its oncogenic signalling.
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Oncogenic signaling by SPHK1 requires phosphorylation-driven translocation to the plasma membrane, not merely increased catalytic activity; the nonphosphorylatable S225A mutant retains full activity but loses transforming ability.
"hSK1 translocation is the key effect of phosphorylation in oncogenic signaling by this enzyme"
SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism.
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SphK1 and SphK2 have opposing roles in ceramide biosynthesis; SphK1 is pro-survival and lowers ceramide.
"Our results demonstrate that SphK1 and SphK2 have opposing roles in the regulation of ceramide biosynthesis"
FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1.
Sphingosine kinase-1 is cleaved by cathepsin B in vitro: identification of the initial cleavage sites for the protease.
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SK1 is a substrate of cathepsin B in vitro, cleaved at His122 and Arg199.
"We identified two initial cleavage sites for the protease, the first at histidine 122 and the second at arginine 199."
Sphingosine 1-phosphate as a regulator of osteoclast differentiation and osteoclast-osteoblast coupling.
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RANKL upregulates SPHK1 and S1P production in osteoclast precursors; SPHK1/S1P has a dichotomous role in osteoclastogenesis.
"the osteoclastogenic factor receptor activator of NF-kappaB ligand (RANKL) upregulated SPHK1 and increased S1P production and secretion."
Eukaryotic elongation factor 1A interacts with sphingosine kinase and directly enhances its catalytic activity.
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eEF1A interacts directly with SK1 and increases its catalytic rate ~3-fold without changing substrate affinities.
"eEF1A is able to directly increase the activity of SK1 and SK2 approximately 3-fold in vitro"
Translocation of sphingosine kinase 1 to the plasma membrane is mediated by calcium- and integrin-binding protein 1.
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CIB1 binds SK1 in a Ca2+-dependent manner at the calmodulin-binding site and translocates SK1 to the plasma membrane (Ca2+-myristoyl switch).
"We show that CIB1 interacts with SK1 in a Ca(2+)-dependent manner at the previously identified "calmodulin-binding site" of SK1."
Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2.
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SPHK1 binds TRAF2; intracellular S1P produced by SPHK1 binds the TRAF2 RING domain and stimulates its E3 ligase activity, driving Lys63 polyubiquitination of RIP1 and NF-kappaB activation, receptor-independently.
"TRAF2 binds to sphingosine kinase 1 (SphK1), one of the isoenzymes that generates the pro-survival lipid mediator sphingosine-1-phosphate (S1P) inside cells."
Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis.
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The GDP-bound form of eEF1A activates SK1; SK1 is required for PTI-1-induced oncogenic transformation.
"eEF1A.GDP, but not eEF1A.GTP, enhancing SK1 activity in vitro"
A critical role for the protein phosphatase 2A B'α regulatory subunit in dephosphorylation of sphingosine kinase 1.
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The PP2A B'alpha (PPP2R5A) regulatory subunit binds the SK1 C-terminus and is required for SK1 dephosphorylation at Ser225, regulating its activity and membrane localization.
"B'α was found to interact with the c-terminus of SK1, and reduce SK1 phosphorylation when overexpressed"
Sphingosine 1-phosphate induces filopodia formation through S1PR2 activation of ERM proteins.
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S1P endogenously generated in a sphingosine-kinase-dependent manner (chiefly SK1) induces ERM phosphorylation and filopodia via the receptor S1PR2 (the receptor activity belongs to S1PR2, not SPHK1).
"endogenously generated S1P (in a sphingosine kinase-dependent manner) results in significant increases in phosphorylation of ERM proteins"
Molecular basis of sphingosine kinase 1 substrate recognition and catalysis.
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Crystal structures of human SphK1 (apo, with substrate-like lipid/ADP, and an inhibitor) reveal a two-domain architecture with the catalytic site in the inter-domain cleft and a hydrophobic lipid-binding pocket.
"Sphingosine kinase 1 (SphK1) is a lipid kinase that catalyzes the conversion of sphingosine to sphingosine-1-phosphate (S1P)"
Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES induction through p38 mitogen-activated protein kinase but independently of nuclear factor κB activation.
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Loss of SK1 prevents TNF-induced p38 MAPK phosphorylation; SK1 suppresses RANTES/CCL5 induction via p38, an anti-inflammatory function separable from NF-kappaB.
"loss of SK1 prevented TNF-induced phosphorylation of p38 MAPK"
Coupling between endocytosis and sphingosine kinase 1 recruitment.
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SPHK1 is recruited to early endocytic intermediates and clathrin-coated pits, is enriched in nerve terminals, and binds negatively charged membranes with a preference for high positive curvature.
"SPHK1 is also targeted to physiologically occurring early endocytic intermediates, and is highly enriched in nerve terminals"
Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons.
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SPHK1 kinase activity on sphingosine increases in the presence of VEGFA in Purkinje cells, linking VEGF signaling to S1P production and autophagosome- lysosome fusion.
"Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C neurons."
Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane Trafficking.
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Sphingosine and its conversion to S1P by SPHK1 are important in endocytic membrane trafficking; SPHK1 is recruited to enlarged endosomes and recruits endophilins.
"our results highlight the importance of sphingosine and its conversion to sphingosine-1-phosphate by SphK1 in endocytic membrane trafficking."
Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease.
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Neuronal SphK1 acetylates COX2/PTGS2, contributing to Alzheimer's disease pathogenesis; SPHK1 is expressed in brain cortex at the protein level.
"Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease."
Sphingolipid de novo biosynthesis
Association of CCT/TriC with sphingosine kinase 1
SPHK1 phosphorylates sphingoid
PKC phosphorylates sphingosine kinase 1
p-SPHK1 phosphorylates sphingosine to sphingosine 1-phosphate
SPHK1 phosphorylates sphingosine in response to E2 stimulation
p-PKR dimer phosphorylates SPHK1
p-S225-SPHK1 localizes to cytosol