ID SPHK1_HUMAN Reviewed; 384 AA. AC Q9NYA1; Q8N632; Q96GK1; Q9HD92; Q9NY70; Q9NYL3; DT 24-OCT-2001, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 27-MAR-2024, entry version 194. DE RecName: Full=Sphingosine kinase 1 {ECO:0000305}; DE Short=SK 1 {ECO:0000303|PubMed:23935096}; DE Short=SPK 1; DE EC=2.7.1.91 {ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659, ECO:0000269|PubMed:24929359}; DE AltName: Full=Acetyltransferase SPHK1; DE EC=2.3.1.-; GN Name=SPHK1 {ECO:0000312|HGNC:HGNC:11240}; GN Synonyms=SK1 {ECO:0000303|PubMed:23935096}, SPHK, SPK; 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 1). RX PubMed=10863092; DOI=10.1016/s0378-1119(00)00205-5; RA Melendez A.J., Carlos-Dias E., Gosink M., Allen J.M., Takacs L.; RT "Human sphingosine kinase: molecular cloning, functional characterization RT and tissue distribution."; RL Gene 251:19-26(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), CATALYTIC ACTIVITY, SUBSTRATE RP SPECIFICITY, AND TISSUE SPECIFICITY. RX PubMed=10802064; DOI=10.1016/s0014-5793(00)01510-6; RA Nava V.E., Lacana' E., Poulton S., Liu H., Sugiura M., Kono K., RA Milstien S., Kohama T., Spiegel S.; RT "Functional characterization of human sphingosine kinase-1."; RL FEBS Lett. 473:81-84(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), SUBSTRATE SPECIFICITY, RP BIOPHYSICOCHEMICAL PROPERTIES, AND COFACTOR. RX PubMed=10947957; DOI=10.1042/bj3500429; RA Pitson S.M., D'Andrea R.J., Vandeleur L., Moretti P.A.B., Xia P., RA Gamble J.R., Vadas M.A., Wattenberg B.W.; RT "Human sphingosine kinase: purification, molecular cloning and RT characterization of the native and recombinant enzymes."; RL Biochem. J. 350:429-441(2000). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Van Veldhoven P.P., Gijsbers S.; RL Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Mammary gland, Ovary, and Testis; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16625196; DOI=10.1038/nature04689; RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R., RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A., RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J., RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J., RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S., RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E., RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K., RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J., RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A., RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D., RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A., RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.; RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the RT human lineage."; RL Nature 440:1045-1049(2006). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3). RC TISSUE=Blood, Kidney, and Skin; 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 [9] RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=11923095; DOI=10.1016/s1388-1981(01)00166-4; RA Gijsbers S., Asselberghs S., Herdewijn P., Van Veldhoven P.P.; RT "1-O-Hexadecyl-2-desoxy-2-amino-sn-glycerol, a substrate for human RT sphingosine kinase."; RL Biochim. Biophys. Acta 1580:1-8(2002). RN [10] RP INTERACTION WITH SPHKAP. RX PubMed=12080051; DOI=10.1074/jbc.m202841200; RA Lacana E., Maceyka M., Milstien S., Spiegel S.; RT "Cloning and characterization of a protein kinase A anchoring protein RT (AKAP)-related protein that interacts with and regulates sphingosine kinase RT 1 activity."; RL J. Biol. Chem. 277:32947-32953(2002). RN [11] RP SUBCELLULAR LOCATION, AND NUCLEAR EXPORT SIGNALS. RX PubMed=14575709; DOI=10.1016/j.bbrc.2003.09.194; RA Inagaki Y., Li P.Y., Wada A., Mitsutake S., Igarashi Y.; RT "Identification of functional nuclear export sequences in human sphingosine RT kinase 1."; RL Biochem. Biophys. Res. Commun. 311:168-173(2003). RN [12] 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 [13] RP INTERACTION WITH EEF1A1, AND BIOPHYSICOCHEMICAL PROPERTIES. 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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-193, AND IDENTIFICATION BY RP 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 INTERACTION WITH CIB1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP 197-PHE-LEU-198. RX PubMed=19854831; DOI=10.1074/jbc.m109.068395; RA Jarman K.E., Moretti P.A., Zebol J.R., Pitson S.M.; RT "Translocation of sphingosine kinase 1 to the plasma membrane is mediated RT by calcium- and integrin-binding protein 1."; RL J. Biol. Chem. 285:483-492(2010). RN [16] RP CATALYTIC ACTIVITY, FUNCTION, INTERACTION WITH TRAF2, MUTAGENESIS OF RP GLY-82, AND PHOSPHORYLATION AT SER-225. RX PubMed=20577214; DOI=10.1038/nature09128; RA Alvarez S.E., Harikumar K.B., Hait N.C., Allegood J., Strub G.M., Kim E.Y., RA Maceyka M., Jiang H., Luo C., Kordula T., Milstien S., Spiegel S.; RT "Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase RT TRAF2."; RL Nature 465:1084-1088(2010). RN [17] RP FUNCTION. RX PubMed=23935096; DOI=10.1074/jbc.m113.489443; RA Adada M.M., Orr-Gandy K.A., Snider A.J., Canals D., Hannun Y.A., RA Obeid L.M., Clarke C.J.; RT "Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES RT induction through p38 mitogen-activated protein kinase but independently of RT nuclear factor kappaB activation."; RL J. Biol. Chem. 288:27667-27679(2013). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF RP LEU-194 AND 197-PHE-LEU-198. RX PubMed=24929359; DOI=10.1038/ncb2987; RA Shen H., Giordano F., Wu Y., Chan J., Zhu C., Milosevic I., Wu X., Yao K., RA Chen B., Baumgart T., Sieburth D., De Camilli P.; RT "Coupling between endocytosis and sphingosine kinase 1 recruitment."; RL Nat. Cell Biol. 16:652-662(2014). RN [19] RP FUNCTION, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY. RX PubMed=25417698; DOI=10.1038/ncomms6514; RA Lee H., Lee J.K., Park M.H., Hong Y.R., Marti H.H., Kim H., Okada Y., RA Otsu M., Seo E.J., Park J.H., Bae J.H., Okino N., He X., Schuchman E.H., RA Bae J.S., Jin H.K.; RT "Pathological roles of the VEGF/SphK pathway in Niemann-Pick type C RT neurons."; RL Nat. Commun. 5:5514-5514(2014). RN [20] RP FUNCTION. RX PubMed=28049734; DOI=10.1074/jbc.m116.762377; RA Lima S., Milstien S., Spiegel S.; RT "Sphingosine and Sphingosine Kinase 1 Involvement in Endocytic Membrane RT Trafficking."; RL J. Biol. Chem. 292:3074-3088(2017). RN [21] RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND FUNCTION. RX PubMed=29662056; DOI=10.1038/s41467-018-03674-2; RA Lee J.Y., Han S.H., Park M.H., Baek B., Song I.S., Choi M.K., Takuwa Y., RA Ryu H., Kim S.H., He X., Schuchman E.H., Bae J.S., Jin H.K.; RT "Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model RT of Alzheimer's Disease."; RL Nat. Commun. 9:1479-1479(2018). RN [22] RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 9-364 IN COMPLEXES WITH SUBSTRATE RP ANALOGS AND ADP, CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF RP ASP-81, AND SUBSTRATE-BINDING REGION. RX PubMed=23602659; DOI=10.1016/j.str.2013.02.025; RA Wang Z., Min X., Xiao S.H., Johnstone S., Romanow W., Meininger D., Xu H., RA Liu J., Dai J., An S., Thibault S., Walker N.; RT "Molecular basis of sphingosine kinase 1 substrate recognition and RT catalysis."; RL Structure 21:798-809(2013). 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 (PubMed:20577214, PubMed:23602659, CC PubMed:29662056, PubMed:24929359, PubMed:11923095). In contrast to CC proapoptotic SPHK2, has a negative effect on intracellular ceramide CC levels, enhances cell growth and inhibits apoptosis (PubMed:16118219). 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:20577214). In response to TNF and in parallel to NF-kappa-B CC activation, negatively regulates RANTES induction through p38 MAPK CC signaling pathway (PubMed:23935096). Involved in endocytic membrane CC trafficking induced by sphingosine, recruited to dilate endosomes, also CC plays a role on later stages of endosomal maturation and membrane CC fusion independently of its kinase activity (PubMed:28049734, CC PubMed:24929359). In Purkinje cells, seems to be also involved in the CC regulation of autophagosome-lysosome fusion upon VEGFA CC (PubMed:25417698). {ECO:0000269|PubMed:11923095, CC ECO:0000269|PubMed:16118219, ECO:0000269|PubMed:20577214, CC ECO:0000269|PubMed:23602659, ECO:0000269|PubMed:23935096, CC ECO:0000269|PubMed:24929359, ECO:0000269|PubMed:25417698, CC ECO:0000269|PubMed:28049734, ECO:0000269|PubMed:29662056}. 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:10802064, CC ECO:0000269|PubMed:20577214, ECO:0000269|PubMed:23602659, CC ECO:0000269|PubMed:24929359, ECO:0000269|PubMed:25417698}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:51497; CC Evidence={ECO:0000269|PubMed:24929359, ECO:0000269|PubMed:25417698}; 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:0000269|PubMed:10802064, CC ECO:0000269|PubMed:11923095}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15466; CC Evidence={ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:11923095}; 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:10802064, ECO:0000269|PubMed:11923095}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35848; CC Evidence={ECO:0000269|PubMed:10802064, ECO:0000269|PubMed:11923095}; 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:0000269|PubMed:11923095}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41164; CC Evidence={ECO:0000269|PubMed:11923095}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10947957}; 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 (PubMed:25417698). In neurons, kinase activity increases during the CC first 24h in presence of Amyloid-beta protein 42 to decrease after 96h CC (By similarity). {ECO:0000250|UniProtKB:Q8CI15, CC ECO:0000250|UniProtKB:Q91V26, ECO:0000269|PubMed:25417698}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=14 uM for sphingosine {ECO:0000269|PubMed:10947957}; CC KM=20 uM for dihydrosphingosine {ECO:0000269|PubMed:10947957}; CC KM=77 uM for ATP {ECO:0000269|PubMed:10947957}; CC KM=3.8 uM for 1-O-hexadecyl-2-amino-sn-glycerol CC {ECO:0000269|PubMed:11923095}; CC KM=15.7 uM for sphing-4-enine {ECO:0000269|PubMed:11923095}; CC KM=46 uM for sphinganine {ECO:0000269|PubMed:11923095}; CC KM=24 uM for sphingosine {ECO:0000269|PubMed:18263879}; CC KM=89 uM for ATP {ECO:0000269|PubMed:18263879}; CC Note=kcat is 124 sec(-1) for sphingosine and increases to 304 sec(-1) CC upon interaction with EEF1A1. {ECO:0000269|PubMed:18263879}; CC pH dependence: CC Optimum pH is 7.4. {ECO:0000269|PubMed:10947957}; CC -!- SUBUNIT: Interacts with ACY1 (By similarity). Binds to calmodulin. CC Interacts with SPHKAP (PubMed:12080051). Interacts with CIB1, the CC interaction occurs in a calcium-dependent manner (PubMed:19854831). CC Interacts with TRAF2 (PubMed:20577214). Interacts with EEF1A1; the CC interaction enhances SPHK1 kinase activity (PubMed:18263879). CC {ECO:0000250|UniProtKB:Q8CI15, ECO:0000269|PubMed:12080051, CC ECO:0000269|PubMed:18263879, ECO:0000269|PubMed:19854831, CC ECO:0000269|PubMed:20577214}. CC -!- INTERACTION: CC Q9NYA1; P07858: CTSB; NbExp=4; IntAct=EBI-985303, EBI-715062; CC Q9NYA1; P68104: EEF1A1; NbExp=2; IntAct=EBI-985303, EBI-352162; CC Q9NYA1; Q14192: FHL2; NbExp=7; IntAct=EBI-985303, EBI-701903; CC Q9NYA1; Q2M3C7: SPHKAP; NbExp=4; IntAct=EBI-985303, EBI-1803914; CC Q9NYA1; Q9Y4K3: TRAF6; NbExp=2; IntAct=EBI-985303, EBI-359276; CC Q9NYA1-2; P13473-2: LAMP2; NbExp=3; IntAct=EBI-12512419, EBI-21591415; CC Q9NYA1-2; Q9Y371: SH3GLB1; NbExp=3; IntAct=EBI-12512419, EBI-2623095; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14575709, CC ECO:0000269|PubMed:19854831, ECO:0000269|PubMed:29662056}. Nucleus CC {ECO:0000269|PubMed:14575709, ECO:0000269|PubMed:19854831, CC ECO:0000269|PubMed:29662056}. Cell membrane CC {ECO:0000269|PubMed:19854831}. Endosome membrane CC {ECO:0000269|PubMed:24929359}; Peripheral membrane protein CC {ECO:0000269|PubMed:24929359}. Membrane, clathrin-coated pit CC {ECO:0000269|PubMed:24929359}. Synapse {ECO:0000250|UniProtKB:Q8CI15}. CC Note=Translocated from the cytoplasm to the plasma membrane in a CIB1- CC dependent manner (PubMed:19854831). Binds to membranes containing CC negatively charged lipids but not neutral lipids (PubMed:24929359). CC Recruited to endocytic membranes by sphingosine where promotes membrane CC fusion (By similarity). {ECO:0000250|UniProtKB:Q8CI15, CC ECO:0000269|PubMed:19854831, ECO:0000269|PubMed:24929359}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9NYA1-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NYA1-2; Sequence=VSP_035453; CC Name=3; CC IsoId=Q9NYA1-3; Sequence=VSP_047078; CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in adult CC liver, kidney, heart and skeletal muscle. Expressed in brain cortex (at CC protein level) (PubMed:29662056). {ECO:0000269|PubMed:10802064, CC ECO:0000269|PubMed:29662056}. 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; AF266756; AAF73470.1; -; mRNA. DR EMBL; AF238083; AAF73423.1; -; mRNA. DR EMBL; AF200328; AAG01980.1; -; mRNA. DR EMBL; AK023393; BAB14558.1; -; mRNA. DR EMBL; AK292294; BAF84983.1; -; mRNA. DR EMBL; AK022402; BAB14028.1; -; mRNA. DR EMBL; AJ245504; CAB92131.1; -; mRNA. DR EMBL; AC090699; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471099; EAW89392.1; -; Genomic_DNA. DR EMBL; CH471099; EAW89393.1; -; Genomic_DNA. DR EMBL; BC009419; AAH09419.1; -; mRNA. DR EMBL; BC014439; AAH14439.1; -; mRNA. DR EMBL; BC030553; AAH30553.1; -; mRNA. DR CCDS; CCDS11744.1; -. [Q9NYA1-2] DR CCDS; CCDS45785.1; -. [Q9NYA1-1] DR CCDS; CCDS59297.1; -. [Q9NYA1-3] DR RefSeq; NP_001136073.1; NM_001142601.1. [Q9NYA1-1] DR RefSeq; NP_001136074.1; NM_001142602.1. [Q9NYA1-1] DR RefSeq; NP_068807.2; NM_021972.3. [Q9NYA1-3] DR RefSeq; NP_892010.2; NM_182965.2. [Q9NYA1-2] DR RefSeq; XP_005257823.1; XM_005257766.2. DR PDB; 3VZB; X-ray; 2.00 A; A/B/C=9-364. DR PDB; 3VZC; X-ray; 2.30 A; A/B/C/D/E/F=9-364. DR PDB; 3VZD; X-ray; 2.30 A; A/B/C/D/E/F=9-364. DR PDB; 4L02; X-ray; 2.75 A; A/B/C=9-364. DR PDB; 4V24; X-ray; 1.80 A; A/B=1-363. DR PDBsum; 3VZB; -. DR PDBsum; 3VZC; -. DR PDBsum; 3VZD; -. DR PDBsum; 4L02; -. DR PDBsum; 4V24; -. DR AlphaFoldDB; Q9NYA1; -. DR SMR; Q9NYA1; -. DR BioGRID; 114396; 52. DR IntAct; Q9NYA1; 61. DR MINT; Q9NYA1; -. DR STRING; 9606.ENSP00000313681; -. DR BindingDB; Q9NYA1; -. DR ChEMBL; CHEMBL4394; -. DR DrugBank; DB08868; Fingolimod. DR GuidetoPHARMACOLOGY; 2204; -. DR SwissLipids; SLP:000000111; -. DR iPTMnet; Q9NYA1; -. DR PhosphoSitePlus; Q9NYA1; -. DR BioMuta; SPHK1; -. DR DMDM; 17369329; -. DR EPD; Q9NYA1; -. DR jPOST; Q9NYA1; -. DR MassIVE; Q9NYA1; -. DR MaxQB; Q9NYA1; -. DR PaxDb; 9606-ENSP00000313681; -. DR PeptideAtlas; Q9NYA1; -. DR ProteomicsDB; 83202; -. [Q9NYA1-1] DR ProteomicsDB; 83203; -. [Q9NYA1-2] DR Pumba; Q9NYA1; -. DR Antibodypedia; 19687; 810 antibodies from 48 providers. DR DNASU; 8877; -. DR Ensembl; ENST00000323374.8; ENSP00000313681.3; ENSG00000176170.14. [Q9NYA1-2] DR Ensembl; ENST00000392496.3; ENSP00000376285.2; ENSG00000176170.14. [Q9NYA1-1] DR Ensembl; ENST00000545180.5; ENSP00000440970.1; ENSG00000176170.14. [Q9NYA1-1] DR Ensembl; ENST00000590959.5; ENSP00000468547.1; ENSG00000176170.14. [Q9NYA1-3] DR Ensembl; ENST00000592299.6; ENSP00000465726.2; ENSG00000176170.14. [Q9NYA1-1] DR GeneID; 8877; -. DR KEGG; hsa:8877; -. DR MANE-Select; ENST00000592299.6; ENSP00000465726.2; NM_001142601.2; NP_001136073.1. DR UCSC; uc002jrf.1; human. [Q9NYA1-1] DR AGR; HGNC:11240; -. DR CTD; 8877; -. DR DisGeNET; 8877; -. DR GeneCards; SPHK1; -. DR HGNC; HGNC:11240; SPHK1. DR HPA; ENSG00000176170; Low tissue specificity. DR MIM; 603730; gene. DR neXtProt; NX_Q9NYA1; -. DR OpenTargets; ENSG00000176170; -. DR PharmGKB; PA36070; -. DR VEuPathDB; HostDB:ENSG00000176170; -. DR eggNOG; KOG1116; Eukaryota. DR GeneTree; ENSGT00940000157864; -. DR HOGENOM; CLU_013399_1_0_1; -. DR InParanoid; Q9NYA1; -. DR OMA; TMGNFYA; -. DR OrthoDB; 374620at2759; -. DR PhylomeDB; Q9NYA1; -. DR TreeFam; TF354296; -. DR BRENDA; 2.7.1.91; 2681. DR PathwayCommons; Q9NYA1; -. DR Reactome; R-HSA-1660661; Sphingolipid de novo biosynthesis. DR Reactome; R-HSA-390471; Association of TriC/CCT with target proteins during biosynthesis. DR Reactome; R-HSA-5218921; VEGFR2 mediated cell proliferation. DR Reactome; R-HSA-9009391; Extra-nuclear estrogen signaling. DR Reactome; R-HSA-9833482; PKR-mediated signaling. DR SABIO-RK; Q9NYA1; -. DR SignaLink; Q9NYA1; -. DR SIGNOR; Q9NYA1; -. DR BioGRID-ORCS; 8877; 19 hits in 1163 CRISPR screens. DR ChiTaRS; SPHK1; human. DR GeneWiki; Sphingosine_kinase_1; -. DR GenomeRNAi; 8877; -. DR Pharos; Q9NYA1; Tchem. DR PRO; PR:Q9NYA1; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q9NYA1; Protein. DR Bgee; ENSG00000176170; Expressed in stromal cell of endometrium and 134 other cell types or tissues. DR ExpressionAtlas; Q9NYA1; baseline and differential. DR GO; GO:0005905; C:clathrin-coated pit; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0031901; C:early endosome membrane; IDA: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:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0098793; C:presynapse; ISS:UniProtKB. DR GO; GO:0016407; F:acetyltransferase activity; ISS:UniProtKB. DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB. DR GO; GO:0005516; F:calmodulin binding; IDA:UniProtKB. DR GO; GO:0017050; F:D-erythro-sphingosine kinase activity; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:MGI. DR GO; GO:0008289; F:lipid binding; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0051721; F:protein phosphatase 2A binding; IPI:BHF-UCL. 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:0019722; P:calcium-mediated signaling; IDA:UniProtKB. DR GO; GO:0008283; P:cell population proliferation; IEA:Ensembl. DR GO; GO:0071363; P:cellular response to growth factor stimulus; IBA:GO_Central. DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IEA:Ensembl. DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IDA:UniProtKB. DR GO; GO:0071897; P:DNA biosynthetic process; IEA:Ensembl. DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl. DR GO; GO:0035556; P:intracellular signal transduction; TAS:UniProtKB. DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:MGI. DR GO; GO:1900060; P:negative regulation of ceramide biosynthetic process; IDA:UniProtKB. DR GO; GO:0016310; P:phosphorylation; IBA:GO_Central. DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB. DR GO; GO:0030307; P:positive regulation of cell growth; IDA:UniProtKB. DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB. DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IDA:MGI. DR GO; GO:0032740; P:positive regulation of interleukin-17 production; ISS:UniProtKB. DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IDA:UniProtKB. DR GO; GO:0045840; P:positive regulation of mitotic nuclear division; IEA:Ensembl. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IMP:UniProtKB. DR GO; GO:1900745; P:positive regulation of p38MAPK cascade; IDA:UniProtKB. DR GO; GO:0010800; P:positive regulation of peptidyl-threonine phosphorylation; IMP:UniProtKB. DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:UniProtKB. DR GO; GO:0045987; P:positive regulation of smooth muscle contraction; IDA:UniProtKB. DR GO; GO:0006473; P:protein acetylation; ISS:UniProtKB. DR GO; GO:0030100; P:regulation of endocytosis; IDA:UniProtKB. DR GO; GO:1905364; P:regulation of endosomal vesicle fusion; ISS:UniProtKB. DR GO; GO:0032651; P:regulation of interleukin-1 beta production; IEA:Ensembl. DR GO; GO:1903978; P:regulation of microglial cell activation; ISS:UniProtKB. DR GO; GO:0150077; P:regulation of neuroinflammatory response; ISS:UniProtKB. DR GO; GO:0050764; P:regulation of phagocytosis; ISS:UniProtKB. DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:0034612; P:response to tumor necrosis factor; IDA:UniProtKB. DR GO; GO:0046521; P:sphingoid catabolic process; NAS: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; 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 PANTHER; PTHR12358; SPHINGOSINE KINASE; 1. DR PANTHER; PTHR12358:SF47; SPHINGOSINE KINASE 1; 1. DR Pfam; PF00781; DAGK_cat; 1. DR SMART; SM00046; DAGKc; 1. DR SUPFAM; SSF111331; NAD kinase/diacylglycerol kinase-like; 1. DR PROSITE; PS50146; DAGK; 1. DR Genevisible; Q9NYA1; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Calmodulin-binding; KW Cell membrane; Coated pit; Cytoplasm; Endosome; Kinase; Lipid metabolism; KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome; KW Synapse; Transferase. FT CHAIN 1..384 FT /note="Sphingosine kinase 1" FT /id="PRO_0000181357" FT DOMAIN 12..159 FT /note="DAGKc" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00783" FT MOTIF 147..155 FT /note="Nuclear export signal 1" FT /evidence="ECO:0000269|PubMed:14575709" FT MOTIF 161..169 FT /note="Nuclear export signal 2" FT /evidence="ECO:0000269|PubMed:14575709" FT ACT_SITE 81 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 22..24 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 54..58 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 79..82 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 86 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 111..113 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 178 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 185 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 191 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT BINDING 341..343 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000269|PubMed:23602659" FT MOD_RES 193 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 225 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:20577214" FT VAR_SEQ 1 FT /note="M -> MSAQVLGFLRSWTPLPLAAPRGPAAAGNDAGAPAATAPGGEGEPHSR FT PCDARLGSTDKELKAGAAATGSAPTAPGTPWQREPRVEVM (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334" FT /id="VSP_035453" FT VAR_SEQ 3 FT /note="P -> PVVGCGRGLFGFVFS (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_047078" FT MUTAGEN 81 FT /note="D->A: Loss of enzyme activity." FT /evidence="ECO:0000269|PubMed:23602659" FT MUTAGEN 81 FT /note="D->N: Strongly reduced enzyme activity." FT /evidence="ECO:0000269|PubMed:23602659" FT MUTAGEN 82 FT /note="G->D: Loss of enzyme activity." FT /evidence="ECO:0000269|PubMed:20577214" FT MUTAGEN 194 FT /note="L->Q: Loss of binding to negatively charged FT membranes, diffuse cytosolic distribution." FT /evidence="ECO:0000269|PubMed:24929359" FT MUTAGEN 197..198 FT /note="FL->AA: Abolishes interaction with CIB1." FT /evidence="ECO:0000269|PubMed:19854831" FT MUTAGEN 197..198 FT /note="FL->AQ: Loss of binding to negatively charged FT membranes, diffuse cytosolic distribution." FT /evidence="ECO:0000269|PubMed:24929359" FT CONFLICT 6 FT /note="Missing (in Ref. 4; CAB92131)" FT /evidence="ECO:0000305" FT CONFLICT 11..15 FT /note="LPRPC -> ARL (in Ref. 4; CAB92131)" FT /evidence="ECO:0000305" FT CONFLICT 114..115 FT /note="NA -> KP (in Ref. 4; CAB92131)" FT /evidence="ECO:0000305" FT CONFLICT 251 FT /note="V -> M (in Ref. 2; AAF73423)" FT /evidence="ECO:0000305" FT CONFLICT 260 FT /note="V -> I (in Ref. 2; AAF73423)" FT /evidence="ECO:0000305" FT CONFLICT 302 FT /note="L -> F (in Ref. 2; AAF73423)" FT /evidence="ECO:0000305" FT CONFLICT 325 FT /note="V -> G (in Ref. 4; CAB92131)" FT /evidence="ECO:0000305" FT CONFLICT 337 FT /note="V -> M (in Ref. 3; AAG01980)" FT /evidence="ECO:0000305" FT STRAND 13..21 FT /evidence="ECO:0007829|PDB:4V24" FT TURN 26..29 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 30..37 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 39..44 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 47..53 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 59..66 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:3VZB" FT STRAND 73..80 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 81..92 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 97..100 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 105..109 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 115..123 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 131..144 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 146..157 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 162..172 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 173..181 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 182..190 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 191..201 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 206..214 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 215..218 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 230..232 FT /evidence="ECO:0007829|PDB:3VZB" FT STRAND 249..251 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 255..266 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 285..291 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 296..305 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 306..308 FT /evidence="ECO:0007829|PDB:4V24" FT HELIX 311..314 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 319..331 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 333..335 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 337..340 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 343..346 FT /evidence="ECO:0007829|PDB:4V24" FT STRAND 350..362 FT /evidence="ECO:0007829|PDB:4V24" FT VARIANT Q9NYA1-2:34 FT /note="A -> T (in dbSNP:rs346803)" FT /evidence="ECO:0000305" FT /id="VAR_082919" SQ SEQUENCE 384 AA; 42518 MW; EB04A7F2034C2DB0 CRC64; MDPAGGPRGV LPRPCRVLVL LNPRGGKGKA LQLFRSHVQP LLAEAEISFT LMLTERRNHA RELVRSEELG RWDALVVMSG DGLMHEVVNG LMERPDWETA IQKPLCSLPA GSGNALAASL NHYAGYEQVT NEDLLTNCTL LLCRRLLSPM NLLSLHTASG LRLFSVLSLA WGFIADVDLE SEKYRRLGEM RFTLGTFLRL AALRTYRGRL AYLPVGRVGS KTPASPVVVQ QGPVDAHLVP LEEPVPSHWT VVPDEDFVLV LALLHSHLGS EMFAAPMGRC AAGVMHLFYV RAGVSRAMLL RLFLAMEKGR HMEYECPYLV YVPVVAFRLE PKDGKGVFAV DGELMVSEAV QGQVHPNYFW MVSGCVEPPP SWKPQQMPPP EEPL //