SPHK2_MOUSE
ID SPHK2_MOUSE Reviewed; 617 AA.
AC Q9JIA7; Q91VA9; Q9DBH6;
DT 24-OCT-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-MAR-2002, sequence version 2.
DT 03-AUG-2022, entry version 175.
DE RecName: Full=Sphingosine kinase 2 {ECO:0000305};
DE Short=SK 2;
DE Short=SPK 2;
DE EC=2.7.1.91 {ECO:0000269|PubMed:10751414, ECO:0000269|PubMed:16118219, ECO:0000269|PubMed:17346996};
GN Name=Sphk2 {ECO:0000312|MGI:MGI:1861380};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CHARACTERIZATION, CATALYTIC ACTIVITY, TISSUE
RP SPECIFICITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE SPECIFICITY, AND
RP FUNCTION.
RC STRAIN=ICR; TISSUE=Brain;
RX PubMed=10751414; DOI=10.1074/jbc.m002759200;
RA Liu H., Sugiura M., Nava V.E., Edsall L.C., Kono K., Poulton S.,
RA Milstien S., Kohama T., Spiegel S.;
RT "Molecular cloning and functional characterization of a novel mammalian
RT sphingosine kinase type 2 isoform.";
RL J. Biol. Chem. 275:19513-19520(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Thompson D., Pyne S.;
RL Submitted (AUG-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Liver;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Limb, and Mammary gland;
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 [5]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF 93-ARG-ARG-94.
RX PubMed=12954646; DOI=10.1074/jbc.m306577200;
RA Igarashi N., Okada T., Hayashi S., Fujita T., Jahangeer S., Nakamura S.;
RT "Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis.";
RL J. Biol. Chem. 278:46832-46839(2003).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF GLY-213 AND LEU-219, AND
RP SUBCELLULAR LOCATION.
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 [7]
RP DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=16314531; DOI=10.1128/mcb.25.24.11113-11121.2005;
RA Mizugishi K., Yamashita T., Olivera A., Miller G.F., Spiegel S.,
RA Proia R.L.;
RT "Essential role for sphingosine kinases in neural and vascular
RT development.";
RL Mol. Cell. Biol. 25:11113-11121(2005).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND CATALYTIC ACTIVITY.
RX PubMed=17346996; DOI=10.1016/j.immuni.2007.02.008;
RA Olivera A., Mizugishi K., Tikhonova A., Ciaccia L., Odom S., Proia R.L.,
RA Rivera J.;
RT "The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of
RT mast cell function and anaphylaxis.";
RL Immunity 26:287-297(2007).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-358; SER-364 AND THR-377, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Spleen, and
RC Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [10]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PHB2.
RX PubMed=20959514; DOI=10.1096/fj.10-167502;
RA Strub G.M., Paillard M., Liang J., Gomez L., Allegood J.C., Hait N.C.,
RA Maceyka M., Price M.M., Chen Q., Simpson D.C., Kordula T., Milstien S.,
RA Lesnefsky E.J., Spiegel S.;
RT "Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria
RT interacts with prohibitin 2 to regulate complex IV assembly and
RT respiration.";
RL FASEB J. 25:600-612(2011).
RN [11]
RP FUNCTION.
RX PubMed=21084291; DOI=10.1074/jbc.m110.171116;
RA Hisano Y., Kobayashi N., Kawahara A., Yamaguchi A., Nishi T.;
RT "The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter
RT of the phosphorylated form of the immunomodulating agent FTY720.";
RL J. Biol. Chem. 286:1758-1766(2011).
RN [12]
RP FUNCTION, TISSUE SPECIFICITY, INDUCTION BY MPTP, AND SUBCELLULAR LOCATION.
RX PubMed=25637806; DOI=10.1016/j.neuroscience.2015.01.032;
RA Sivasubramanian M., Kanagaraj N., Dheen S.T., Tay S.S.;
RT "Sphingosine kinase 2 and sphingosine-1-phosphate promotes mitochondrial
RT function in dopaminergic neurons of mouse model of Parkinson's disease and
RT in MPP+ -treated MN9D cells in vitro.";
RL Neuroscience 290:636-648(2015).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30593892; DOI=10.1016/j.bbadis.2018.12.012;
RA Ravichandran S., Finlin B.S., Kern P.A., Oezcan S.;
RT "Sphk2-/- mice are protected from obesity and insulin resistance.";
RL Biochim. Biophys. Acta 1865:570-576(2019).
CC -!- FUNCTION: Catalyzes the phosphorylation of sphingosine to form
CC sphingosine-1-phosphate (SPP), a lipid mediator with both intra- and
CC extracellular functions (PubMed:16118219, PubMed:17346996,
CC PubMed:21084291). Also acts on D-erythro-dihydrosphingosine, D-erythro-
CC sphingosine and L-threo-dihydrosphingosine. Binds phosphoinositides
CC (PubMed:16118219, PubMed:10751414). In contrast to prosurvival SPHK1,
CC has a positive effect on intracellular ceramide levels, inhibits cells
CC growth and enhances apoptosis (PubMed:16118219). In mitochondria, is
CC important for cytochrome-c oxidase assembly and mitochondrial
CC respiration. The SPP produced in mitochondria binds PHB2 and modulates
CC the regulation via PHB2 of complex IV assembly and respiration
CC (PubMed:20959514). In nucleus, plays a role in epigenetic regulation of
CC gene expression. Interacts with HDAC1 and HDAC2 and, through SPP
CC production, inhibits their enzymatic activity, preventing the removal
CC of acetyl groups from lysine residues with histones. Up-regulates
CC acetylation of histone H3-K9, histone H4-K5 and histone H2B-K12. In
CC nucleus, may have an inhibitory effect on DNA synthesis and cell cycle
CC (By similarity). In mast cells, is the main regulator of SPP production
CC which mediates calcium influx, NF-kappa-B activation, cytokine
CC production, such as TNF and IL6, and degranulation of mast cells
CC (PubMed:17346996). In dopaminergic neurons, is involved in promoting
CC mitochondrial functions regulating ATP and ROS levels
CC (PubMed:25637806). Also involved in the regulation of glucose and lipid
CC metabolism (PubMed:30593892). {ECO:0000250|UniProtKB:Q9NRA0,
CC ECO:0000269|PubMed:10751414, ECO:0000269|PubMed:16118219,
CC ECO:0000269|PubMed:17346996, ECO:0000269|PubMed:20959514,
CC ECO:0000269|PubMed:21084291, ECO:0000269|PubMed:25637806,
CC ECO:0000269|PubMed:30593892}.
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:0000269|PubMed:17346996};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51497;
CC Evidence={ECO:0000269|PubMed:17346996};
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:0000269|PubMed:10751414};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35848;
CC Evidence={ECO:0000269|PubMed:10751414};
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:0000269|PubMed:10751414};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15466;
CC Evidence={ECO:0000269|PubMed:10751414};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(4R)-hydroxysphinganine + ATP = (4R)-hydroxysphinganine 1-
CC phosphate + ADP + H(+); Xref=Rhea:RHEA:33563, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:64124, ChEBI:CHEBI:64795,
CC ChEBI:CHEBI:456216; EC=2.7.1.91;
CC Evidence={ECO:0000269|PubMed:10751414};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33564;
CC Evidence={ECO:0000269|PubMed:10751414};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=3.4 uM for sphing-4-enine {ECO:0000269|PubMed:10751414};
CC Vmax=0.1 nmol/min/mg enzyme {ECO:0000269|PubMed:10751414};
CC Vmax=0.3 nmol/min/mg enzyme (in the presence of 50 mM KCl);
CC Vmax=1 nmol/min/mg enzyme (in the presence of 200 mM KCl);
CC pH dependence:
CC Optimum pH is 7.5. {ECO:0000269|PubMed:10751414};
CC -!- SUBUNIT: Interacts with histone H3. Interacts with HDAC1, HDAC2, MBD2
CC and SIN3A. Interacts with EEF1A1; the interaction enhances SPHK2 kinase
CC activity (By similarity). Interacts with PHB2 (PubMed:20959514).
CC {ECO:0000250|UniProtKB:Q9NRA0, ECO:0000269|PubMed:20959514}.
CC -!- INTERACTION:
CC Q9JIA7; P39688: Fyn; NbExp=2; IntAct=EBI-985434, EBI-524514;
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:Q9NRA0}.
CC Cytoplasm {ECO:0000269|PubMed:12954646, ECO:0000269|PubMed:16118219}.
CC Cell membrane {ECO:0000269|PubMed:16118219}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:16118219}. Nucleus {ECO:0000269|PubMed:12954646,
CC ECO:0000269|PubMed:20959514}. Mitochondrion inner membrane
CC {ECO:0000269|PubMed:20959514, ECO:0000269|PubMed:25637806}. Note=In
CC nucleus, is located in nucleosomes where it associates with core
CC histone proteins such as histone 3. In apoptotic cells, colocalizes
CC with CASP1 in cell membrane where is cleaved and released from cells in
CC an active form. {ECO:0000250|UniProtKB:Q9NRA0}.
CC -!- TISSUE SPECIFICITY: Expressed in heart, brain, liver, kidney and testis
CC (PubMed:10751414). Expressed by mast cells (at protein level)
CC (PubMed:17346996). In the substantia nigra, expressed by dopaminergic
CC neurons (at protein level) (PubMed:25637806).
CC {ECO:0000269|PubMed:10751414, ECO:0000269|PubMed:17346996,
CC ECO:0000269|PubMed:25637806}.
CC -!- DEVELOPMENTAL STAGE: At 10.5 dpc, expression is relatively ubiquitous
CC with the strongest signals detected in the limb buds, eyes and
CC branchial arches and a weaker expression in the telencephalon and
CC spinal cord. {ECO:0000269|PubMed:16314531}.
CC -!- INDUCTION: Expressopm decreases upon treatment with 1-methyl-4-phenyl-
CC 1,2,3,6-tetrahydropyridine (MPTP) which is used to induce Parkinson
CC disease in mouse model. {ECO:0000269|PubMed:25637806}.
CC -!- PTM: Phosphorylated by PKD on Ser-384 and Ser-386 upon PMA treatment.
CC Phosphorylation induces export from the nucleus to the cytoplasm.
CC Phosphorylated by MAPK1 and MAPK2 at Thr-578, phosphorylation is
CC induced by agonists such as EGF and PMA and increases kinase activity.
CC {ECO:0000250|UniProtKB:Q9NRA0}.
CC -!- PTM: Cleaved by CASP1 in apoptotic cells. The truncated form is
CC released from cells. {ECO:0000250|UniProtKB:Q9NRA0}.
CC -!- DISRUPTION PHENOTYPE: Mutant mice are viable, fertile and have normal
CC longevity. They show reduced SPP levels (PubMed:16314531). Mice have
CC decreased fat mass but increased lean mass, they display increased
CC energy expenditure compared to wild-type. Aging mice are protected from
CC metabolic decline and obesity. 52-week old male mutant mice have
CC decreased weight and fat mass, and increased glucose tolerance and
CC insulin sensitivity compared to control mice (PubMed:30593892). Double
CC knockout for SPHK1 and SPHK2 causes embryonic lethality
CC (PubMed:16314531). Between 11.5 dpc and 12.5 dpc embryos exhibit
CC cranial hemorrhage and die at 13.5 dpc (PubMed:16314531). At 11.5 dpc
CC the wall of the dorsal aorta is poorly developed and endothelial cells
CC are severely defective in all blood vessels in the mesenchymal region
CC of the head (PubMed:16314531). Embryos also show a neural tube defect
CC (PubMed:16314531). {ECO:0000269|PubMed:16314531,
CC ECO:0000269|PubMed:30593892}.
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DR EMBL; AF245448; AAF74125.1; -; mRNA.
DR EMBL; AF415214; AAL07500.1; -; mRNA.
DR EMBL; AK004951; BAB23694.1; -; mRNA.
DR EMBL; BC006941; AAH06941.1; -; mRNA.
DR EMBL; BC053737; AAH53737.1; -; mRNA.
DR CCDS; CCDS21261.1; -.
DR RefSeq; NP_001166032.1; NM_001172561.1.
DR RefSeq; NP_064395.2; NM_020011.5.
DR RefSeq; NP_975009.1; NM_203280.3.
DR RefSeq; XP_006541075.1; XM_006541012.3.
DR RefSeq; XP_006541076.1; XM_006541013.3.
DR AlphaFoldDB; Q9JIA7; -.
DR SMR; Q9JIA7; -.
DR IntAct; Q9JIA7; 5.
DR STRING; 10090.ENSMUSP00000072615; -.
DR BindingDB; Q9JIA7; -.
DR ChEMBL; CHEMBL1075305; -.
DR SwissLipids; SLP:000000113; -.
DR iPTMnet; Q9JIA7; -.
DR PhosphoSitePlus; Q9JIA7; -.
DR SwissPalm; Q9JIA7; -.
DR EPD; Q9JIA7; -.
DR jPOST; Q9JIA7; -.
DR MaxQB; Q9JIA7; -.
DR PaxDb; Q9JIA7; -.
DR PRIDE; Q9JIA7; -.
DR ProteomicsDB; 261572; -.
DR Antibodypedia; 31745; 458 antibodies from 37 providers.
DR DNASU; 56632; -.
DR Ensembl; ENSMUST00000072836; ENSMUSP00000072615; ENSMUSG00000057342.
DR Ensembl; ENSMUST00000107737; ENSMUSP00000103366; ENSMUSG00000057342.
DR Ensembl; ENSMUST00000210060; ENSMUSP00000147391; ENSMUSG00000057342.
DR GeneID; 56632; -.
DR KEGG; mmu:56632; -.
DR UCSC; uc009gwt.2; mouse.
DR CTD; 56848; -.
DR MGI; MGI:1861380; Sphk2.
DR VEuPathDB; HostDB:ENSMUSG00000057342; -.
DR eggNOG; KOG1116; Eukaryota.
DR GeneTree; ENSGT00940000161197; -.
DR HOGENOM; CLU_013399_1_1_1; -.
DR InParanoid; Q9JIA7; -.
DR OMA; AHHCNEP; -.
DR OrthoDB; 681139at2759; -.
DR PhylomeDB; Q9JIA7; -.
DR TreeFam; TF354296; -.
DR BRENDA; 2.7.1.91; 3474.
DR Reactome; R-MMU-1660661; Sphingolipid de novo biosynthesis.
DR SABIO-RK; Q9JIA7; -.
DR BioGRID-ORCS; 56632; 6 hits in 73 CRISPR screens.
DR ChiTaRS; Sphk2; mouse.
DR PRO; PR:Q9JIA7; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q9JIA7; protein.
DR Bgee; ENSMUSG00000057342; Expressed in saccule of membranous labyrinth and 235 other tissues.
DR ExpressionAtlas; Q9JIA7; baseline and differential.
DR Genevisible; Q9JIA7; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0000786; C:nucleosome; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0017050; F:D-erythro-sphingosine kinase activity; IDA:UniProtKB.
DR GO; GO:0042393; F:histone binding; ISO:MGI.
DR GO; GO:0001727; F:lipid kinase activity; IBA:GO_Central.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0008481; F:sphinganine kinase activity; ISS:UniProtKB.
DR GO; GO:0038036; F:sphingosine-1-phosphate receptor activity; ISO:MGI.
DR GO; GO:0001568; P:blood vessel development; IGI:MGI.
DR GO; GO:0007420; P:brain development; IGI:MGI.
DR GO; GO:0008283; P:cell population proliferation; IGI:MGI.
DR GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; ISS:UniProtKB.
DR GO; GO:0045815; P:epigenetic maintenance of chromatin in transcription-competent conformation; ISS:UniProtKB.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0043977; P:histone H2A-K5 acetylation; ISS:UniProtKB.
DR GO; GO:0043980; P:histone H2B-K12 acetylation; ISS:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:1901726; P:negative regulation of histone deacetylase activity; ISS:UniProtKB.
DR GO; GO:0031064; P:negative regulation of histone deacetylation; ISS:UniProtKB.
DR GO; GO:0016310; P:phosphorylation; IBA:GO_Central.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0090280; P:positive regulation of calcium ion import; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IGI:MGI.
DR GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; IMP:UniProtKB.
DR GO; GO:2000617; P:positive regulation of histone H3-K9 acetylation; ISS:UniProtKB.
DR GO; GO:0032736; P:positive regulation of interleukin-13 production; IMP:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IMP:UniProtKB.
DR GO; GO:0033008; P:positive regulation of mast cell activation involved in immune response; IMP:UniProtKB.
DR GO; GO:0043306; P:positive regulation of mast cell degranulation; IMP:UniProtKB.
DR GO; GO:0090037; P:positive regulation of protein kinase C signaling; IMP:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IMP:UniProtKB.
DR GO; GO:2001169; P:regulation of ATP biosynthetic process; IMP:UniProtKB.
DR GO; GO:1904959; P:regulation of cytochrome-c oxidase activity; IMP:UniProtKB.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IMP:UniProtKB.
DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; IMP:UniProtKB.
DR GO; GO:0006669; P:sphinganine-1-phosphate biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006665; P:sphingolipid metabolic process; IBA:GO_Central.
DR GO; GO:0046512; P:sphingosine biosynthetic process; ISO:MGI.
DR GO; GO:0006670; P:sphingosine metabolic process; IMP: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 InterPro; IPR045540; YegS/DAGK_C.
DR Pfam; PF00781; DAGK_cat; 1.
DR Pfam; PF19279; YegS_C; 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; Cell membrane; Cytoplasm; Endoplasmic reticulum; Kinase;
KW Lipid metabolism; Lysosome; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..617
FT /note="Sphingosine kinase 2"
FT /id="PRO_0000181359"
FT DOMAIN 143..290
FT /note="DAGKc"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT REGION 1..140
FT /note="Required for binding to sulfatide and
FT phosphoinositides and for membrane localization"
FT /evidence="ECO:0000250|UniProtKB:Q9NRA0"
FT REGION 371..472
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 87..95
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:12954646"
FT MOTIF 381..390
FT /note="Nuclear export signal"
FT /evidence="ECO:0000250|UniProtKB:Q9NRA0"
FT ACT_SITE 212
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 153..155
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 185..189
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 210..213
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 217
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 242..244
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 309
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 316
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 322
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 586..588
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT MOD_RES 358
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 364
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 377
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 384
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NRA0"
FT MOD_RES 386
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9NRA0"
FT MOD_RES 578
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9NRA0"
FT MUTAGEN 93..94
FT /note="RR->EE: Loss of nuclear location. Loss of DNA
FT synthesis inhibition."
FT /evidence="ECO:0000269|PubMed:12954646"
FT MUTAGEN 213
FT /note="G->E: Abolishes sphingosine kinase activity.
FT Decreases apoptosis induction. Abolishes sphingosine kinase
FT activity. No effect on endoplasmic reticulum location
FT increase upon serum starvation. Abolishes sphingosine
FT kinase activity and decreases apoptosis induction; when
FT associated with A-219."
FT /evidence="ECO:0000269|PubMed:16118219"
FT MUTAGEN 219
FT /note="L->A: Strongly decreases sphingosine kinase
FT activity. Decreases apoptosis induction. No effect on
FT endoplasmic reticulum location increase upon serum
FT starvation. Abolishes sphingosine kinase activity and
FT decreases apoptosis induction; when associated with E-213."
FT /evidence="ECO:0000269|PubMed:16118219"
FT CONFLICT 252
FT /note="N -> S (in Ref. 1; AAF74125)"
FT /evidence="ECO:0000305"
FT CONFLICT 510
FT /note="P -> T (in Ref. 1; AAF74125)"
FT /evidence="ECO:0000305"
FT CONFLICT 548
FT /note="L -> F (in Ref. 1; AAF74125)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 617 AA; 65618 MW; 40EE2C2C288BE26A CRC64;
MAPPPLLPVA ASTPILHGEF GSYPANGPRF ALTLTTQALH IQRLRPKPEA RPRDGLVSLD
EVSGCGTLQS RSPEDTAAYF CIYTYPRGRR GGRRRATRTF RADGATTYEE NRAEAQRWAT
ALTCLLRGVP LSGDQEITPE LLPRKPRLLI LVNPFGGRGL AWQRCMDHVV PMISEAGLSF
NLIQTERQNH ARELVQGLSL SEWEGIVTVS GDGLLYEVLN GLLDRPDWED AVRMPIGVLP
CGSGNALAGA VNHHGGFEQV VGVDLLLNCS LLLCRGGSHP LDLLSVTLAS GSRCFSFLSV
AWGFLSDVDI HSERFRALGS ARFTLGAVLG LASLHTYRGR LSYLPATTEP ALPIPGHSLP
RAKSELVLAP APAPAATHSP LHRSVSDLPL PLPQPALVSP GSPEPLPDLS LNGGGPELTG
DWGGAGDAPL SPDPLLPSSP NALKTAQLSP IAEGPPEMPA SSGFLPPTHS APEASTWGPV
DHLLPPLGSP LPQDWVTIEG EFVLMLGILP SHLCADLMAA PHARFDDGVV HLCWVRSGIS
RAALLRILLA MEHGNHFSLG CPHLGYAAAR AFRLEPLTPR GLLTVDGELV EYGPIQAQVH
PGLATLLTGP AGQKPQA
