SPHK1_RAT
ID SPHK1_RAT Reviewed; 383 AA.
AC Q91V26; Q642F6;
DT 20-MAY-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 118.
DE RecName: Full=Sphingosine kinase 1;
DE Short=SK 1;
DE Short=SPK 1;
DE EC=2.7.1.91 {ECO:0000269|PubMed:16118219};
DE AltName: Full=Acetyltransferase SPHK1;
DE EC=2.3.1.-;
GN Name=Sphk1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11560121; DOI=10.1006/geno.2001.6607;
RA Imamura T., Ohgane J., Ito S., Ogawa T., Hattori N., Tanaka S., Shiota K.;
RT "CpG island of rat sphingosine kinase-1 gene: tissue-dependent DNA
RT methylation status and multiple alternative first exons.";
RL Genomics 76:117-125(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP SUBCELLULAR LOCATION, MUTAGENESIS OF GLY-82, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=16118219; DOI=10.1074/jbc.m502207200;
RA Maceyka M., Sankala H., Hait N.C., Le Stunff H., Liu H., Toman R.,
RA Collier C., Zhang M., Satin L.S., Merrill A.H. Jr., Milstien S.,
RA Spiegel S.;
RT "SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in
RT sphingolipid metabolism.";
RL J. Biol. Chem. 280:37118-37129(2005).
RN [4]
RP FUNCTION, INDUCTION BY AMYLOID-BETA PROTEIN 42, ACTIVITY REGULATION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=26334640; DOI=10.1371/journal.pone.0137193;
RA Cieslik M., Czapski G.A., Strosznajder J.B.;
RT "The Molecular Mechanism of Amyloid beta42 Peptide Toxicity: The Role of
RT Sphingosine Kinase-1 and Mitochondrial Sirtuins.";
RL PLoS ONE 10:E0137193-E0137193(2015).
RN [5]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=28284343; DOI=10.1016/j.jneuroim.2017.01.015;
RA Su D., Cheng Y., Li S., Dai D., Zhang W., Lv M.;
RT "Sphk1 mediates neuroinflammation and neuronal injury via TRAF2/NF-kappaB
RT pathways in activated microglia in cerebral ischemia reperfusion.";
RL J. Neuroimmunol. 305:35-41(2017).
CC -!- FUNCTION: Catalyzes the phosphorylation of sphingosine to form
CC sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and
CC extracellular functions. Also acts on D-erythro-sphingosine and to a
CC lesser extent sphinganine, but not other lipids, such as D,L-threo-
CC dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide,
CC or phosphatidylinositol (Probable) (PubMed:16118219). In contrast to
CC proapoptotic SPHK2, has a negative effect on intracellular ceramide
CC levels, enhances cell growth and inhibits apoptosis (By similarity).
CC Involved in the regulation of inflammatory response and
CC neuroinflammation. Via the product sphingosine 1-phosphate, stimulates
CC TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-
CC kappa-B in response to TNF signaling leading to IL17 secretion
CC (PubMed:28284343). In response to TNF and in parallel to NF-kappa-B
CC activation, negatively regulates RANTES induction through p38 MAPK
CC signaling pathway. Involved in endocytic membrane trafficking induced
CC by sphingosine, recruited to dilate endosomes, also plays a role on
CC later stages of endosomal maturation and membrane fusion independently
CC of its kinase activity. In Purkinje cells, seems to be also involved in
CC the regulation of autophagosome-lysosome fusion upon VEGFA (By
CC similarity). {ECO:0000250|UniProtKB:Q9NYA1,
CC ECO:0000269|PubMed:16118219, ECO:0000269|PubMed:28284343,
CC ECO:0000305|PubMed:26334640}.
CC -!- FUNCTION: Has serine acetyltransferase activity on PTGS2/COX2 in an
CC acetyl-CoA dependent manner. The acetyltransferase activity increases
CC in presence of the kinase substrate, sphingosine. During
CC neuroinflammation, through PTGS2 acetylation, promotes neuronal
CC secretion of specialized preresolving mediators (SPMs), especially 15-
CC R-lipoxin A4, which results in an increase of phagocytic microglia.
CC {ECO:0000250|UniProtKB:Q8CI15}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingoid base + ATP = a sphingoid 1-phosphate + ADP + H(+);
CC Xref=Rhea:RHEA:51496, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:76941, ChEBI:CHEBI:84410, ChEBI:CHEBI:456216;
CC EC=2.7.1.91; Evidence={ECO:0000269|PubMed:16118219,
CC ECO:0000305|PubMed:26334640};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51497;
CC Evidence={ECO:0000269|PubMed:16118219};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + L-seryl-[protein] = CoA + O-acetyl-L-seryl-
CC [protein]; Xref=Rhea:RHEA:59392, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:15352, ChEBI:CHEBI:29999, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:141128; Evidence={ECO:0000250|UniProtKB:Q8CI15};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:59393;
CC Evidence={ECO:0000250|UniProtKB:Q8CI15};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + sphinganine = ADP + H(+) + sphinganine 1-phosphate;
CC Xref=Rhea:RHEA:15465, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:57817, ChEBI:CHEBI:57939, ChEBI:CHEBI:456216;
CC EC=2.7.1.91; Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + sphing-4-enine = ADP + H(+) + sphing-4-enine 1-
CC phosphate; Xref=Rhea:RHEA:35847, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:57756, ChEBI:CHEBI:60119,
CC ChEBI:CHEBI:456216; EC=2.7.1.91;
CC Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1-O-hexadecyl-2-amino-sn-glycerol + ATP = 1-O-hexadecyl-2-
CC desoxy-2-amino-sn-glycero-3-phosphate + ADP + H(+);
CC Xref=Rhea:RHEA:41163, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:77786, ChEBI:CHEBI:77787, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC -!- ACTIVITY REGULATION: Acetyltransferase activity increases in presence
CC of the kinase substrate, sphingosine (By similarity). In Purkinje
CC cells, kinase activity on sphingosine increases in presence of VEGFA
CC (By similarity). In neurons, kinase activity increases during the first
CC 24h in presence of Amyloid-beta protein 42 to decrease after 96h
CC (PubMed:26334640). {ECO:0000250|UniProtKB:Q8CI15,
CC ECO:0000250|UniProtKB:Q9NYA1, ECO:0000269|PubMed:26334640}.
CC -!- SUBUNIT: Interacts with ACY1 (By similarity). Binds to calmodulin.
CC Interacts with SPHKAP (By similarity). Interacts with CIB1, the
CC interaction occurs in a calcium-dependent manner. Interacts with TRAF2
CC (By similarity). Interacts with EEF1A1; the interaction enhances SPHK1
CC kinase activity (By similarity). {ECO:0000250|UniProtKB:Q8CI15,
CC ECO:0000250|UniProtKB:Q9NYA1}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:16118219}. Nucleus
CC {ECO:0000250|UniProtKB:Q9NYA1}. Cell membrane
CC {ECO:0000250|UniProtKB:Q9NYA1}. Endosome membrane
CC {ECO:0000250|UniProtKB:Q9NYA1}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:Q9NYA1}. Membrane, clathrin-coated pit
CC {ECO:0000250|UniProtKB:Q9NYA1}. Synapse {ECO:0000250|UniProtKB:Q8CI15}.
CC Note=Translocated from the cytoplasm to the plasma membrane in a CIB1-
CC dependent manner. Binds to membranes containing negatively charged
CC lipids but not neutral lipids (By similarity). Recruited to endocytic
CC membranes by sphingosine where promotes membrane fusion (By
CC similarity). {ECO:0000250|UniProtKB:Q8CI15,
CC ECO:0000250|UniProtKB:Q9NYA1}.
CC -!- TISSUE SPECIFICITY: Expressed in microglia (at protein level).
CC {ECO:0000269|PubMed:28284343}.
CC -!- INDUCTION: In neurons, expression increases during the first 24h in
CC presence of Amyloid-beta protein 42 to decrease after 96h.
CC {ECO:0000269|PubMed:26334640}.
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DR EMBL; AB049571; BAB62320.1; -; mRNA.
DR EMBL; AB049572; BAB62321.1; -; mRNA.
DR EMBL; AB049573; BAB62322.1; -; mRNA.
DR EMBL; AB049574; BAB62323.1; -; mRNA.
DR EMBL; AB049575; BAB62324.1; -; mRNA.
DR EMBL; BC081738; AAH81738.1; -; mRNA.
DR RefSeq; NP_001257736.1; NM_001270807.1.
DR RefSeq; NP_001257737.1; NM_001270808.1.
DR RefSeq; NP_001257738.1; NM_001270809.1.
DR RefSeq; NP_001257739.1; NM_001270810.1.
DR RefSeq; NP_001257740.1; NM_001270811.1.
DR RefSeq; NP_596877.2; NM_133386.3.
DR AlphaFoldDB; Q91V26; -.
DR SMR; Q91V26; -.
DR IntAct; Q91V26; 1.
DR STRING; 10116.ENSRNOP00000029296; -.
DR ChEMBL; CHEMBL1075107; -.
DR iPTMnet; Q91V26; -.
DR PhosphoSitePlus; Q91V26; -.
DR PaxDb; Q91V26; -.
DR GeneID; 170897; -.
DR KEGG; rno:170897; -.
DR CTD; 8877; -.
DR RGD; 620048; Sphk1.
DR eggNOG; KOG1116; Eukaryota.
DR InParanoid; Q91V26; -.
DR OrthoDB; 681139at2759; -.
DR PhylomeDB; Q91V26; -.
DR BRENDA; 2.7.1.91; 5301.
DR Reactome; R-RNO-1660661; Sphingolipid de novo biosynthesis.
DR Reactome; R-RNO-390471; Association of TriC/CCT with target proteins during biosynthesis.
DR Reactome; R-RNO-5218921; VEGFR2 mediated cell proliferation.
DR Reactome; R-RNO-9009391; Extra-nuclear estrogen signaling.
DR SABIO-RK; Q91V26; -.
DR PRO; PR:Q91V26; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030424; C:axon; IDA:RGD.
DR GO; GO:0005905; C:clathrin-coated pit; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:RGD.
DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB.
DR GO; GO:0030139; C:endocytic vesicle; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0043005; C:neuron projection; IDA:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:RGD.
DR GO; GO:0098793; C:presynapse; ISO:RGD.
DR GO; GO:0008021; C:synaptic vesicle; IDA:RGD.
DR GO; GO:0016407; F:acetyltransferase activity; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; ISO:RGD.
DR GO; GO:0005516; F:calmodulin binding; ISO:RGD.
DR GO; GO:0017050; F:D-erythro-sphingosine kinase activity; IDA:RGD.
DR GO; GO:0003677; F:DNA binding; ISO:RGD.
DR GO; GO:0008289; F:lipid binding; ISS:UniProtKB.
DR GO; GO:0001727; F:lipid kinase activity; IBA:GO_Central.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0051721; F:protein phosphatase 2A binding; ISO:RGD.
DR GO; GO:0008481; F:sphinganine kinase activity; ISS:UniProtKB.
DR GO; GO:0038036; F:sphingosine-1-phosphate receptor activity; ISO:RGD.
DR GO; GO:0001568; P:blood vessel development; ISO:RGD.
DR GO; GO:0007420; P:brain development; ISO:RGD.
DR GO; GO:0019722; P:calcium-mediated signaling; ISO:RGD.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEP:RGD.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEP:RGD.
DR GO; GO:0009267; P:cellular response to starvation; IEP:RGD.
DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0019371; P:cyclooxygenase pathway; IDA:RGD.
DR GO; GO:0071897; P:DNA biosynthetic process; ISO:RGD.
DR GO; GO:0007565; P:female pregnancy; IEP:RGD.
DR GO; GO:0006954; P:inflammatory response; ISO:RGD.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:RGD.
DR GO; GO:1900060; P:negative regulation of ceramide biosynthetic process; ISS:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; ISO:RGD.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:RGD.
DR GO; GO:0030307; P:positive regulation of cell growth; ISO:RGD.
DR GO; GO:0030335; P:positive regulation of cell migration; IMP:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; ISO:RGD.
DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IMP:UniProtKB.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISO:RGD.
DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; ISO:RGD.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD.
DR GO; GO:0001956; P:positive regulation of neurotransmitter secretion; IMP:RGD.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; ISS:UniProtKB.
DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; ISO:RGD.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:RGD.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; ISS:UniProtKB.
DR GO; GO:0045987; P:positive regulation of smooth muscle contraction; ISO:RGD.
DR GO; GO:0006473; P:protein acetylation; ISS:UniProtKB.
DR GO; GO:0030100; P:regulation of endocytosis; ISS:UniProtKB.
DR GO; GO:1905364; P:regulation of endosomal vesicle fusion; ISS:UniProtKB.
DR GO; GO:0032651; P:regulation of interleukin-1 beta production; ISO:RGD.
DR GO; GO:1903978; P:regulation of microglial cell activation; ISS:UniProtKB.
DR GO; GO:0150077; P:regulation of neuroinflammatory response; IMP:UniProtKB.
DR GO; GO:0050764; P:regulation of phagocytosis; ISS:UniProtKB.
DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0014075; P:response to amine; IEP:RGD.
DR GO; GO:0033198; P:response to ATP; IEP:RGD.
DR GO; GO:0070555; P:response to interleukin-1; IEP:RGD.
DR GO; GO:0032026; P:response to magnesium ion; IEP:RGD.
DR GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR GO; GO:0032570; P:response to progesterone; IEP:RGD.
DR GO; GO:0034612; P:response to tumor necrosis factor; ISS:UniProtKB.
DR GO; GO:0090520; P:sphingolipid mediated signaling pathway; ISO:RGD.
DR GO; GO:0006665; P:sphingolipid metabolic process; IBA:GO_Central.
DR GO; GO:0046512; P:sphingosine biosynthetic process; ISO:RGD.
DR GO; GO:0006670; P:sphingosine metabolic process; ISS:UniProtKB.
DR Gene3D; 3.40.50.10330; -; 1.
DR InterPro; IPR017438; ATP-NAD_kinase_N.
DR InterPro; IPR001206; Diacylglycerol_kinase_cat_dom.
DR InterPro; IPR016064; NAD/diacylglycerol_kinase_sf.
DR Pfam; PF00781; DAGK_cat; 1.
DR SMART; SM00046; DAGKc; 1.
DR SUPFAM; SSF111331; SSF111331; 1.
DR PROSITE; PS50146; DAGK; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Calmodulin-binding; Cell membrane; Coated pit; Cytoplasm;
KW Endosome; Kinase; Lipid metabolism; Membrane; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Synapse; Transferase.
FT CHAIN 1..383
FT /note="Sphingosine kinase 1"
FT /id="PRO_0000333033"
FT DOMAIN 12..159
FT /note="DAGKc"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT REGION 363..383
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 147..155
FT /note="Nuclear export signal 1"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT MOTIF 161..169
FT /note="Nuclear export signal 2"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT ACT_SITE 81
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 22..24
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 54..58
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 79..82
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 86
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 111..113
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 178
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 185
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 191
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 340..342
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT MOD_RES 193
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT MOD_RES 225
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT MUTAGEN 82
FT /note="G->D: Loss of sphingosine kinase activity."
FT /evidence="ECO:0000269|PubMed:16118219"
FT CONFLICT 299
FT /note="V -> L (in Ref. 2; AAH81738)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 383 AA; 42418 MW; CAAD5817BF4B9507 CRC64;
MQPADCPRGL LPRPCRVLVL LNPRGGKGKA LKLFQSRVRP LLEEAEVSFK LMLTERQNHA
RELVCAEELG HWDALAVMSG DGLMHEVVNG LMERPDWESA IQKPLCSLPG GSGNALAASL
NYYAGHEQVT NEDLLINCTL LLCCRQLSPM NLLSLHTASG RQLYSVLSLS WGFVADVDLE
SEKYRSLGEI RFTVGTFFRL ASLRIYQGQL AYLPVGKAAS KIPASSLAQK GPANTYLVPL
EEPVPPHWTV VPEQDFVLVL VLLHTHLSTE MFAAPMGRCE AGVMHLFYIR AGVSRAMLVR
LFLAMQKGKH MDLDCPYLVH VPVVAFRLEP RNQRGVFSVD GELMVCEAVQ GQVHPNYLWM
VSGSSDSPSG RDSQRRPPPE EPI
