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 27-MAR-2024, entry version 190. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_011525435.1; XM_011527133.1. DR RefSeq; XP_011525436.1; XM_011527134.1. DR AlphaFoldDB; Q9NRA0; -. DR SMR; Q9NRA0; -. DR BioGRID; 121208; 21. DR IntAct; Q9NRA0; 7. DR STRING; 9606.ENSP00000469158; -. DR BindingDB; Q9NRA0; -. DR ChEMBL; CHEMBL3023; -. DR DrugBank; DB12764; Opaganib. DR GuidetoPHARMACOLOGY; 2205; -. DR SwissLipids; SLP:000000112; -. DR iPTMnet; Q9NRA0; -. DR PhosphoSitePlus; Q9NRA0; -. DR SwissPalm; Q9NRA0; -. DR BioMuta; SPHK2; -. DR DMDM; 22001996; -. DR EPD; Q9NRA0; -. DR jPOST; Q9NRA0; -. DR MassIVE; Q9NRA0; -. DR MaxQB; Q9NRA0; -. DR PaxDb; 9606-ENSP00000245222; -. DR PeptideAtlas; Q9NRA0; -. DR ProteomicsDB; 82315; -. [Q9NRA0-1] DR ProteomicsDB; 82316; -. [Q9NRA0-2] DR ProteomicsDB; 82317; -. [Q9NRA0-3] DR ProteomicsDB; 86; -. DR Pumba; Q9NRA0; -. DR Antibodypedia; 31745; 545 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 AGR; HGNC:18859; -. 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; GQEANED; -. DR OrthoDB; 374620at2759; -. 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; 27 hits in 1164 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 145 other cell types or tissues. DR ExpressionAtlas; Q9NRA0; baseline and differential. 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: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:0030308; P:negative regulation of cell growth; 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; 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: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:0043122; P:regulation of canonical NF-kappaB signal transduction; ISS:UniProtKB. DR GO; GO:1904959; P:regulation of cytochrome-c oxidase activity; IMP: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:0046512; P:sphingosine biosynthetic process; IMP:UniProtKB. DR GO; GO:0006670; P:sphingosine metabolic process; ISS:UniProtKB. DR GO; GO:0045815; P:transcription initiation-coupled chromatin remodeling; IDA:UniProtKB. DR Gene3D; 2.60.200.40; -; 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 PANTHER; PTHR12358; SPHINGOSINE KINASE; 1. DR PANTHER; PTHR12358:SF40; SPHINGOSINE KINASE 2; 1. DR Pfam; PF00781; DAGK_cat; 1. DR Pfam; PF19279; YegS_C; 1. DR SMART; SM00046; DAGKc; 1. DR SUPFAM; SSF111331; NAD kinase/diacylglycerol kinase-like; 1. DR PROSITE; PS50146; DAGK; 1. DR Genevisible; Q9NRA0; HS. 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 activity." 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 //