SPHK2_HUMAN
ID SPHK2_HUMAN Reviewed; 654 AA.
AC Q9NRA0; A0T4C8; B4DU87; Q9BRN1; Q9H0Q2; Q9NWU7;
DT 24-OCT-2001, integrated into UniProtKB/Swiss-Prot.
DT 26-JUL-2002, sequence version 2.
DT 03-AUG-2022, entry version 181.
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:12954646, ECO:0000269|PubMed:19729656};
GN Name=SPHK2 {ECO:0000312|HGNC:HGNC:18859}; Synonyms=SK2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), CATALYTIC ACTIVITY, SUBSTRATE
RP SPECIFICITY, AND TISSUE SPECIFICITY.
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] (ISOFORM 5).
RA Alemany R., Ruemenapp U., van Koppen C.J., Danneberg K.,
RA Meyer zu Heringdorf D., Jakobs K.H.;
RT "Variant of human sphingosine kinase-2 (SPHK2).";
RL Submitted (NOV-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 1-354 (ISOFORM 3).
RC TISSUE=Carcinoma, and Prostate;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Eye, and Lymph;
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 [7]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
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 [8]
RP ALTERNATIVE SPLICING, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=16103110; DOI=10.1074/jbc.m504507200;
RA Okada T., Ding G., Sonoda H., Kajimoto T., Haga Y., Khosrowbeygi A.,
RA Gao S., Miwa N., Jahangeer S., Nakamura S.;
RT "Involvement of N-terminal-extended form of sphingosine kinase 2 in serum-
RT dependent regulation of cell proliferation and apoptosis.";
RL J. Biol. Chem. 280:36318-36325(2005).
RN [9]
RP FUNCTION.
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 [10]
RP PHOSPHORYLATION AT SER-387 AND THR-614, MUTAGENESIS OF SER-387; SER-437;
RP SER-466; SER-477 AND THR-614, AND ACTIVITY REGULATION.
RX PubMed=17311928; DOI=10.1074/jbc.m609559200;
RA Hait N.C., Bellamy A., Milstien S., Kordula T., Spiegel S.;
RT "Sphingosine kinase type 2 activation by ERK-mediated phosphorylation.";
RL J. Biol. Chem. 282:12058-12065(2007).
RN [11]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-419 AND SER-421, AND
RP MUTAGENESIS OF 419-SER--SER-421 AND 423-LEU--LEU-425.
RX PubMed=17635916; DOI=10.1074/jbc.m701641200;
RA Ding G., Sonoda H., Yu H., Kajimoto T., Goparaju S.K., Jahangeer S.,
RA Okada T., Nakamura S.;
RT "Protein kinase D-mediated phosphorylation and nuclear export of
RT sphingosine kinase 2.";
RL J. Biol. Chem. 282:27493-27502(2007).
RN [12]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS] (ISOFORM 2).
RC TISSUE=Placenta;
RX PubMed=17897319; DOI=10.1111/j.1600-0854.2007.00643.x;
RA Schroeder B., Wrocklage C., Pan C., Jaeger R., Koesters B., Schaefer H.,
RA Elsaesser H.-P., Mann M., Hasilik A.;
RT "Integral and associated lysosomal membrane proteins.";
RL Traffic 8:1676-1686(2007).
RN [13]
RP INTERACTION WITH EEF1A1.
RX PubMed=18263879; DOI=10.1074/jbc.m708782200;
RA Leclercq T.M., Moretti P.A., Vadas M.A., Pitson S.M.;
RT "Eukaryotic elongation factor 1A interacts with sphingosine kinase and
RT directly enhances its catalytic activity.";
RL J. Biol. Chem. 283:9606-9614(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP FUNCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND REGION.
RX PubMed=19168031; DOI=10.1016/j.bbrc.2009.01.075;
RA Don A.S., Rosen H.;
RT "A lipid binding domain in sphingosine kinase 2.";
RL Biochem. Biophys. Res. Commun. 380:87-92(2009).
RN [16]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH HISTONE H3; HDAC1; HDAC2;
RP MBD2 AND SIN3A, MUTAGENESIS OF GLY-212, AND CATALYTIC ACTIVITY.
RX PubMed=19729656; DOI=10.1126/science.1176709;
RA Hait N.C., Allegood J., Maceyka M., Strub G.M., Harikumar K.B., Singh S.K.,
RA Luo C., Marmorstein R., Kordula T., Milstien S., Spiegel S.;
RT "Regulation of histone acetylation in the nucleus by sphingosine-1-
RT phosphate.";
RL Science 325:1254-1257(2009).
RN [17]
RP SUBCELLULAR LOCATION, CLEAVAGE, AND MUTAGENESIS OF ASP-138; THR-220 AND
RP ASP-552.
RX PubMed=20197547; DOI=10.1182/blood-2009-10-243444;
RA Weigert A., Cremer S., Schmidt M.V., von Knethen A., Angioni C.,
RA Geisslinger G., Bruene B.;
RT "Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from
RT apoptotic cells.";
RL Blood 115:3531-3540(2010).
RN [18]
RP FUNCTION.
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 [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-387 AND SER-399, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-477, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [21]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=29615132; DOI=10.1186/s40478-018-0527-z;
RA Dominguez G., Maddelein M.L., Pucelle M., Nicaise Y., Maurage C.A.,
RA Duyckaerts C., Cuvillier O., Delisle M.B.;
RT "Neuronal sphingosine kinase 2 subcellular localization is altered in
RT Alzheimer's disease brain.";
RL Acta Neuropathol. Commun. 6:25-25(2018).
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-dihydrosphingosine, D-
CC erythro-sphingosine and L-threo-dihydrosphingosine. Binds
CC phosphoinositides (PubMed:19168031, PubMed:12954646). In contrast to
CC prosurvival SPHK1, has a positive effect on intracellular ceramide
CC levels, inhibits cells growth and enhances apoptosis (PubMed:16118219).
CC In mitochondria, is important for cytochrome-c oxidase assembly and
CC mitochondrial respiration. The SPP produced in mitochondria binds PHB2
CC and modulates the regulation via PHB2 of complex IV assembly and
CC respiration (PubMed:20959514). In nucleus, plays a role in epigenetic
CC regulation of gene expression. Interacts with HDAC1 and HDAC2 and,
CC through SPP production, inhibits their enzymatic activity, preventing
CC the removal of acetyl groups from lysine residues with histones. Up-
CC regulates acetylation of histone H3-K9, histone H4-K5 and histone H2B-
CC K12 (PubMed:19729656). In nucleus, may have an inhibitory effect on DNA
CC synthesis and cell cycle (PubMed:12954646, PubMed:16103110). In mast
CC cells, is the main regulator of SPP production which mediates calcium
CC influx, NF-kappa-B activation, cytokine production, such as TNF and
CC IL6, and degranulation of mast cells (By similarity). In dopaminergic
CC neurons, is involved in promoting mitochondrial functions regulating
CC ATP and ROS levels (By similarity). Also involved in the regulation of
CC glucose and lipid metabolism (By similarity).
CC {ECO:0000250|UniProtKB:Q9JIA7, ECO:0000269|PubMed:12954646,
CC ECO:0000269|PubMed:16103110, ECO:0000269|PubMed:16118219,
CC ECO:0000269|PubMed:19168031, ECO:0000269|PubMed:19729656,
CC ECO:0000269|PubMed:20959514}.
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:10751414,
CC ECO:0000269|PubMed:12954646, ECO:0000269|PubMed:19729656};
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:0000250|UniProtKB:Q9JIA7};
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:0000250|UniProtKB:Q9JIA7};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9NYA1};
CC -!- ACTIVITY REGULATION: Inhibited by sulfatide (PubMed:19168031). Kinase
CC activity is increased by phosphorylation by MAPK2 upon PMA or EGF
CC treatments (PubMed:17311928). {ECO:0000269|PubMed:17311928,
CC ECO:0000269|PubMed:19168031}.
CC -!- SUBUNIT: Interacts with histone H3 (PubMed:19729656). Interacts with
CC HDAC1, HDAC2, MBD2 and SIN3A (PubMed:19729656). Interacts with EEF1A1;
CC the interaction enhances SPHK2 kinase activity (PubMed:18263879).
CC Interacts with PHB2 (By similarity). {ECO:0000250|UniProtKB:Q9JIA7,
CC ECO:0000269|PubMed:18263879, ECO:0000269|PubMed:19729656}.
CC -!- INTERACTION:
CC Q9NRA0; Q96CV9: OPTN; NbExp=3; IntAct=EBI-985324, EBI-748974;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:12954646,
CC ECO:0000269|PubMed:16103110, ECO:0000269|PubMed:17635916,
CC ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:29615132}. Nucleus
CC {ECO:0000269|PubMed:12954646, ECO:0000269|PubMed:16103110,
CC ECO:0000269|PubMed:17635916, ECO:0000269|PubMed:19729656,
CC ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:29615132}. Endoplasmic
CC reticulum {ECO:0000250|UniProtKB:Q9JIA7}. Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:Q9JIA7}. Note=In nucleus, located in nucleosomes
CC where it associates with core histone proteins such as histone 3
CC (PubMed:19729656). In brains of patients with Alzheimer's disease, may
CC be preferentially localized in the nucleus. Cytosolic expression
CC decrease correlates with the density of amyloid deposits
CC (PubMed:29615132). In apoptotic cells, colocalizes with CASP1 in cell
CC membrane where is cleaved and released from cells in an active form
CC (PubMed:20197547). {ECO:0000269|PubMed:19729656,
CC ECO:0000269|PubMed:20197547, ECO:0000269|PubMed:29615132}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Lysosome membrane
CC {ECO:0000269|PubMed:17897319}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Experimental confirmation may be lacking for some isoforms.;
CC Name=1; Synonyms=SK2B, SK2-L {ECO:0000303|PubMed:16103110};
CC IsoId=Q9NRA0-1; Sequence=Displayed;
CC Name=2; Synonyms=SK2A, SK2-S {ECO:0000303|PubMed:16103110};
CC IsoId=Q9NRA0-2; Sequence=VSP_006217;
CC Name=3;
CC IsoId=Q9NRA0-3; Sequence=VSP_006217, VSP_006218;
CC Name=4;
CC IsoId=Q9NRA0-4; Sequence=VSP_046910;
CC Name=5;
CC IsoId=Q9NRA0-5; Sequence=VSP_047721, VSP_047722;
CC -!- TISSUE SPECIFICITY: Mainly expressed in adult kidney, liver, and brain
CC (PubMed:10751414). Expressed in cerebral cortex and hippocampus (at
CC protein level) (PubMed:29615132). Isoform 1 is the predominant form
CC expressed in most tissues (PubMed:16103110).
CC {ECO:0000269|PubMed:10751414, ECO:0000269|PubMed:16103110,
CC ECO:0000269|PubMed:29615132}.
CC -!- PTM: Phosphorylated by PKD on Ser-419 and Ser-421 upon PMA treatment.
CC Phosphorylation induces export from the nucleus to the cytoplasm
CC (PubMed:17635916). Phosphorylated by MAPK1 and MAPK2 at Ser-387 and
CC Thr-614, phosphorylation is induced by agonists such as EGF and PMA and
CC increases kinase activity (PubMed:17311928).
CC {ECO:0000269|PubMed:17311928, ECO:0000269|PubMed:17635916}.
CC -!- PTM: Cleaved by CASP1 in apoptotic cells. The truncated form is
CC released from cells. {ECO:0000269|PubMed:20197547}.
CC -!- DISEASE: Note=In patients with Alzheimer's disease brains, may be
CC preferentially localized in the nucleus. Cytosolic expression decrease
CC correlates with the density of amyloid deposits.
CC {ECO:0000269|PubMed:29615132}.
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DR EMBL; AF245447; AAF74124.1; -; mRNA.
DR EMBL; EF107108; ABK81123.1; -; mRNA.
DR EMBL; AL136701; CAB66636.1; -; mRNA.
DR EMBL; AK000599; BAA91280.1; -; mRNA.
DR EMBL; AK300541; BAG62249.1; -; mRNA.
DR EMBL; AC022154; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC006161; AAH06161.1; -; mRNA.
DR EMBL; BC010671; AAH10671.1; -; mRNA.
DR CCDS; CCDS12727.1; -. [Q9NRA0-1]
DR CCDS; CCDS59404.1; -. [Q9NRA0-4]
DR CCDS; CCDS59405.1; -. [Q9NRA0-2]
DR RefSeq; NP_001191087.1; NM_001204158.2. [Q9NRA0-4]
DR RefSeq; NP_001191088.1; NM_001204159.2. [Q9NRA0-1]
DR RefSeq; NP_001191089.1; NM_001204160.2. [Q9NRA0-2]
DR RefSeq; NP_064511.2; NM_020126.4. [Q9NRA0-1]
DR RefSeq; XP_006723355.1; XM_006723292.1. [Q9NRA0-2]
DR RefSeq; XP_011525435.1; XM_011527133.1. [Q9NRA0-1]
DR RefSeq; XP_011525436.1; XM_011527134.1. [Q9NRA0-2]
DR AlphaFoldDB; Q9NRA0; -.
DR SMR; Q9NRA0; -.
DR BioGRID; 121208; 20.
DR IntAct; Q9NRA0; 7.
DR STRING; 9606.ENSP00000245222; -.
DR BindingDB; Q9NRA0; -.
DR ChEMBL; CHEMBL3023; -.
DR DrugBank; DB12764; Opaganib.
DR GuidetoPHARMACOLOGY; 2205; -.
DR SwissLipids; SLP:000000112; -.
DR iPTMnet; Q9NRA0; -.
DR PhosphoSitePlus; Q9NRA0; -.
DR BioMuta; SPHK2; -.
DR DMDM; 22001996; -.
DR EPD; Q9NRA0; -.
DR jPOST; Q9NRA0; -.
DR MassIVE; Q9NRA0; -.
DR MaxQB; Q9NRA0; -.
DR PaxDb; Q9NRA0; -.
DR PeptideAtlas; Q9NRA0; -.
DR PRIDE; Q9NRA0; -.
DR ProteomicsDB; 82315; -. [Q9NRA0-1]
DR ProteomicsDB; 82316; -. [Q9NRA0-2]
DR ProteomicsDB; 82317; -. [Q9NRA0-3]
DR ProteomicsDB; 86; -.
DR Antibodypedia; 31745; 458 antibodies from 37 providers.
DR DNASU; 56848; -.
DR Ensembl; ENST00000245222.9; ENSP00000245222.3; ENSG00000063176.16. [Q9NRA0-1]
DR Ensembl; ENST00000598088.5; ENSP00000469158.1; ENSG00000063176.16. [Q9NRA0-1]
DR Ensembl; ENST00000599748.5; ENSP00000471205.1; ENSG00000063176.16. [Q9NRA0-2]
DR Ensembl; ENST00000600537.5; ENSP00000470092.1; ENSG00000063176.16. [Q9NRA0-4]
DR GeneID; 56848; -.
DR KEGG; hsa:56848; -.
DR MANE-Select; ENST00000245222.9; ENSP00000245222.3; NM_020126.5; NP_064511.2.
DR UCSC; uc002pjr.4; human. [Q9NRA0-1]
DR CTD; 56848; -.
DR DisGeNET; 56848; -.
DR GeneCards; SPHK2; -.
DR HGNC; HGNC:18859; SPHK2.
DR HPA; ENSG00000063176; Low tissue specificity.
DR MIM; 607092; gene.
DR neXtProt; NX_Q9NRA0; -.
DR OpenTargets; ENSG00000063176; -.
DR PharmGKB; PA38719; -.
DR VEuPathDB; HostDB:ENSG00000063176; -.
DR eggNOG; KOG1116; Eukaryota.
DR GeneTree; ENSGT00940000161197; -.
DR HOGENOM; CLU_013399_1_1_1; -.
DR InParanoid; Q9NRA0; -.
DR OMA; EREDGMM; -.
DR OrthoDB; 681139at2759; -.
DR PhylomeDB; Q9NRA0; -.
DR TreeFam; TF354296; -.
DR BRENDA; 2.7.1.91; 2681.
DR PathwayCommons; Q9NRA0; -.
DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis.
DR SignaLink; Q9NRA0; -.
DR SIGNOR; Q9NRA0; -.
DR BioGRID-ORCS; 56848; 26 hits in 1083 CRISPR screens.
DR ChiTaRS; SPHK2; human.
DR GeneWiki; SPHK2; -.
DR GenomeRNAi; 56848; -.
DR Pharos; Q9NRA0; Tchem.
DR PRO; PR:Q9NRA0; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9NRA0; protein.
DR Bgee; ENSG00000063176; Expressed in mucosa of transverse colon and 144 other tissues.
DR ExpressionAtlas; Q9NRA0; baseline and differential.
DR Genevisible; Q9NRA0; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; IDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0000786; C:nucleosome; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
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; IDA:GO_Central.
DR GO; GO:0001727; F:lipid kinase activity; IBA:GO_Central.
DR GO; GO:0003951; F:NAD+ kinase activity; IEA:InterPro.
DR GO; GO:0031267; F:small GTPase binding; NAS:UniProtKB.
DR GO; GO:0008481; F:sphinganine kinase activity; IDA:UniProtKB.
DR GO; GO:0038036; F:sphingosine-1-phosphate receptor activity; IMP:UniProtKB.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0007420; P:brain development; IEA:Ensembl.
DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl.
DR GO; GO:1904628; P:cellular response to phorbol 13-acetate 12-myristate; IDA:UniProtKB.
DR GO; GO:0045815; P:epigenetic maintenance of chromatin in transcription-competent conformation; IDA:UniProtKB.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0043977; P:histone H2A-K5 acetylation; IDA:UniProtKB.
DR GO; GO:0043980; P:histone H2B-K12 acetylation; IDA:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; ISS:UniProtKB.
DR GO; GO:1901726; P:negative regulation of histone deacetylase activity; IDA:UniProtKB.
DR GO; GO:0031064; P:negative regulation of histone deacetylation; IDA: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; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IEA:Ensembl.
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; ISS:UniProtKB.
DR GO; GO:2000617; P:positive regulation of histone H3-K9 acetylation; IDA:UniProtKB.
DR GO; GO:0032736; P:positive regulation of interleukin-13 production; ISS:UniProtKB.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISS:UniProtKB.
DR GO; GO:0033008; P:positive regulation of mast cell activation involved in immune response; ISS:UniProtKB.
DR GO; GO:0043306; P:positive regulation of mast cell degranulation; ISS:UniProtKB.
DR GO; GO:0090037; P:positive regulation of protein kinase C signaling; ISS:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:UniProtKB.
DR GO; GO:2001169; P:regulation of ATP biosynthetic process; ISS: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; ISS:UniProtKB.
DR GO; GO:1903426; P:regulation of reactive oxygen species biosynthetic process; ISS:UniProtKB.
DR GO; GO:0006669; P:sphinganine-1-phosphate biosynthetic process; IDA:UniProtKB.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
DR GO; GO:0006665; P:sphingolipid metabolic process; IBA:GO_Central.
DR GO; GO:0046512; P:sphingosine biosynthetic process; IMP:UniProtKB.
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 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 Alternative splicing; ATP-binding; Cytoplasm; Endoplasmic reticulum;
KW Kinase; Lipid metabolism; Lysosome; Membrane; Mitochondrion;
KW Mitochondrion inner membrane; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Transferase.
FT CHAIN 1..654
FT /note="Sphingosine kinase 2"
FT /id="PRO_0000181358"
FT DOMAIN 178..325
FT /note="DAGKc"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT REGION 1..175
FT /note="Required for binding to sulfatide and
FT phosphoinositides and for membrane localizatione"
FT /evidence="ECO:0000269|PubMed:19168031"
FT REGION 1..28
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 400..509
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 122..130
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q9JIA7"
FT MOTIF 416..425
FT /note="Nuclear export signal"
FT /evidence="ECO:0000269|PubMed:17635916"
FT COMPBIAS 1..15
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 247
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 188..190
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 220..224
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 245..248
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 252
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 277..279
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 344
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9NYA1"
FT BINDING 351
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 357
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT BINDING 622..624
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783"
FT MOD_RES 387
FT /note="Phosphoserine; by MAPK"
FT /evidence="ECO:0000269|PubMed:17311928,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 393
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JIA7"
FT MOD_RES 399
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 419
FT /note="Phosphoserine; by PKD"
FT /evidence="ECO:0000269|PubMed:17635916"
FT MOD_RES 421
FT /note="Phosphoserine; by PKD"
FT /evidence="ECO:0000269|PubMed:17635916"
FT MOD_RES 477
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 614
FT /note="Phosphothreonine; by MAPK"
FT /evidence="ECO:0000269|PubMed:17311928"
FT VAR_SEQ 1..36
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:10751414,
FT ECO:0000303|PubMed:11230166, ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_006217"
FT VAR_SEQ 1..12
FT /note="MNGHLEAEEQQD -> MIGCLHARVSGPLWDAGLCPASSRSAHTCLSLSVSD
FT APVSPATAPHCLLLSTAPAPPCPCHGVLNSHPFSPPFP (in isoform 5)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_047721"
FT VAR_SEQ 13..71
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046910"
FT VAR_SEQ 292..390
FT /note="FEPALGLDLLLNCSLLLCRGGGHPLDLLSVTLASGSRCFSFLSVAWGFVSDV
FT DIQSERFRALGSARFTLGTVLGLATLHTYRGRLSYLPATVEPASPTP -> PREDSDSS
FT TSSSACPLWTTARSCPRAAASMPGSCPLLPQQLALGFSRFIQDRVNGGGGRIGSLTCRG
FT HTQRTLPAPAREGGGSLFLKNINVFICKKKKK (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_006218"
FT VAR_SEQ 640..654
FT /note="GTLLTGPPGCPGREP -> ARGRTQTPALPAAPALYGRQPGAAHGLQPVCQG
FT AALFFHNSWLWGSQDLFRIVLTEAVGG (in isoform 5)"
FT /evidence="ECO:0000303|Ref.2"
FT /id="VSP_047722"
FT VARIANT 652
FT /note="R -> Q (in dbSNP:rs11881285)"
FT /id="VAR_060112"
FT MUTAGEN 138
FT /note="D->A: Abolishes cleavage and secretion in apoptotic
FT cells. No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:20197547"
FT MUTAGEN 212
FT /note="G->E: Decreases SPP production in nucleus. Abolishes
FT increase of histone acetylation. No effect on association
FT with histone 3."
FT /evidence="ECO:0000269|PubMed:19729656"
FT MUTAGEN 220
FT /note="T->A: Loss of location to cell membrane. Not
FT secreted. No effect on kinase acitivity."
FT /evidence="ECO:0000269|PubMed:20197547"
FT MUTAGEN 387
FT /note="S->A: Strongly reduces phosphorylation levels."
FT /evidence="ECO:0000269|PubMed:17311928"
FT MUTAGEN 419..421
FT /note="SVS->AVA: Abolishes nuclear export in response to
FT PMA treatment."
FT /evidence="ECO:0000269|PubMed:17635916"
FT MUTAGEN 423..425
FT /note="LPL->APA: Abolishes nuclear export."
FT /evidence="ECO:0000269|PubMed:17635916"
FT MUTAGEN 437
FT /note="S->A: Reduces phosphorylation levels."
FT /evidence="ECO:0000269|PubMed:17311928"
FT MUTAGEN 466
FT /note="S->A: Reduces phosphorylation levels."
FT /evidence="ECO:0000269|PubMed:17311928"
FT MUTAGEN 477
FT /note="S->A: Reduces phosphorylation levels."
FT /evidence="ECO:0000269|PubMed:17311928"
FT MUTAGEN 552
FT /note="D->A: No effect on cleavage and secretion in
FT apoptotic cells. No effect on kinase activity."
FT /evidence="ECO:0000269|PubMed:20197547"
FT MUTAGEN 614
FT /note="T->A: Abolishes phosphorylation."
FT /evidence="ECO:0000269|PubMed:17311928"
FT CONFLICT 49
FT /note="P -> S (in Ref. 3; CAB66636)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 654 AA; 69217 MW; F73FFCEC930DA50F CRC64;
MNGHLEAEEQ QDQRPDQELT GSWGHGPRST LVRAKAMAPP PPPLAASTPL LHGEFGSYPA
RGPRFALTLT SQALHIQRLR PKPEARPRGG LVPLAEVSGC CTLRSRSPSD SAAYFCIYTY
PRGRRGARRR ATRTFRADGA ATYEENRAEA QRWATALTCL LRGLPLPGDG EITPDLLPRP
PRLLLLVNPF GGRGLAWQWC KNHVLPMISE AGLSFNLIQT ERQNHARELV QGLSLSEWDG
IVTVSGDGLL HEVLNGLLDR PDWEEAVKMP VGILPCGSGN ALAGAVNQHG GFEPALGLDL
LLNCSLLLCR GGGHPLDLLS VTLASGSRCF SFLSVAWGFV SDVDIQSERF RALGSARFTL
GTVLGLATLH TYRGRLSYLP ATVEPASPTP AHSLPRAKSE LTLTPDPAPP MAHSPLHRSV
SDLPLPLPQP ALASPGSPEP LPILSLNGGG PELAGDWGGA GDAPLSPDPL LSSPPGSPKA
ALHSPVSEGA PVIPPSSGLP LPTPDARVGA STCGPPDHLL PPLGTPLPPD WVTLEGDFVL
MLAISPSHLG ADLVAAPHAR FDDGLVHLCW VRSGISRAAL LRLFLAMERG SHFSLGCPQL
GYAAARAFRL EPLTPRGVLT VDGEQVEYGP LQAQMHPGIG TLLTGPPGCP GREP
