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Protein

Sphingosine kinase 1

Gene

SPHK1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the phosphorylation of sphingosine to form sphingosine 1-phosphate (SPP), a lipid mediator with both intra- and extracellular functions. Also acts on D-erythro-sphingosine and to a lesser extent sphinganine, but not other lipids, such as D,L-threo-dihydrosphingosine, N,N-dimethylsphingosine, diacylglycerol, ceramide, or phosphatidylinositol.2 Publications

Miscellaneous

Sphingosine 1-phosphate stimulates TRAF2 E3 ubiquitin ligase activity, and promotes activation of NF-kappa-B in response to TNF signaling.

Catalytic activityi

ATP + a sphingoid base = ADP + a sphingoid base 1-phosphate.3 Publications

Cofactori

Mg2+1 Publication

Kineticsi

  1. KM=14 µM for sphingosine1 Publication
  2. KM=20 µM for dihydrosphingosine1 Publication
  3. KM=77 µM for ATP1 Publication

    pH dependencei

    Optimum pH is 7.4.1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei81Proton donor/acceptor1 Publication1
    Binding sitei86ATP1
    Binding sitei178Substrate1
    Binding sitei185ATP1
    Binding sitei191ATP1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi22 – 24ATP3
    Nucleotide bindingi54 – 58ATP5
    Nucleotide bindingi111 – 113ATP3
    Nucleotide bindingi341 – 343ATP3

    GO - Molecular functioni

    • ATP binding Source: UniProtKB
    • calmodulin binding Source: UniProtKB
    • D-erythro-sphingosine kinase activity Source: UniProtKB
    • DNA binding Source: MGI
    • magnesium ion binding Source: UniProtKB
    • NAD+ kinase activity Source: InterPro
    • protein phosphatase 2A binding Source: BHF-UCL
    • sphinganine kinase activity Source: MGI
    • sphingosine-1-phosphate receptor activity Source: UniProtKB

    GO - Biological processi

    • blood vessel development Source: Ensembl
    • brain development Source: Ensembl
    • calcium-mediated signaling Source: UniProtKB
    • inflammatory response Source: Ensembl
    • intracellular signal transduction Source: UniProtKB
    • negative regulation of apoptotic process Source: MGI
    • positive regulation of angiogenesis Source: UniProtKB
    • positive regulation of cell growth Source: UniProtKB
    • positive regulation of cell migration Source: UniProtKB
    • positive regulation of fibroblast proliferation Source: MGI
    • positive regulation of mitotic cell cycle Source: UniProtKB
    • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
    • positive regulation of NIK/NF-kappaB signaling Source: UniProtKB
    • positive regulation of peptidyl-threonine phosphorylation Source: UniProtKB
    • positive regulation of protein ubiquitination Source: UniProtKB
    • positive regulation of smooth muscle contraction Source: UniProtKB
    • protein folding Source: Reactome
    • regulation of interleukin-1 beta production Source: Ensembl
    • regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
    • signal transduction Source: ProtInc
    • sphingoid catabolic process Source: UniProtKB
    • sphingolipid biosynthetic process Source: Reactome
    • sphingosine biosynthetic process Source: UniProtKB
    • sphingosine metabolic process Source: UniProtKB

    Keywordsi

    Molecular functionCalmodulin-binding, Kinase, Transferase
    LigandATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi2.7.1.91 2681
    ReactomeiR-HSA-1660661 Sphingolipid de novo biosynthesis
    R-HSA-390471 Association of TriC/CCT with target proteins during biosynthesis
    R-HSA-5218921 VEGFR2 mediated cell proliferation
    SABIO-RKiQ9NYA1
    SignaLinkiQ9NYA1
    SIGNORiQ9NYA1

    Chemistry databases

    SwissLipidsiSLP:000000111

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Sphingosine kinase 1 (EC:2.7.1.913 Publications)
    Short name:
    SK 1
    Short name:
    SPK 1
    Gene namesi
    Name:SPHK1
    Synonyms:SPHK, SPK
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 17

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000176170.13
    HGNCiHGNC:11240 SPHK1
    MIMi603730 gene
    neXtProtiNX_Q9NYA1

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi81D → A: Loss of enzyme activity. 1 Publication1
    Mutagenesisi81D → N: Strongly reduced enzyme activity. 1 Publication1
    Mutagenesisi82G → D: Loss of enzyme activity. 1 Publication1
    Mutagenesisi197F → A: Abolishes interaction with CIB1; when associated with A-198. 1
    Mutagenesisi198L → A: Abolishes interaction with CIB1; when associated with A-197. 1

    Organism-specific databases

    DisGeNETi8877
    OpenTargetsiENSG00000176170
    PharmGKBiPA36070

    Chemistry databases

    ChEMBLiCHEMBL4394
    DrugBankiDB08868 Fingolimod
    GuidetoPHARMACOLOGYi2204

    Polymorphism and mutation databases

    BioMutaiSPHK1
    DMDMi17369329

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001813571 – 384Sphingosine kinase 1Add BLAST384

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei193PhosphothreonineCombined sources1
    Modified residuei225Phosphoserine1 Publication1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiQ9NYA1
    PaxDbiQ9NYA1
    PeptideAtlasiQ9NYA1
    PRIDEiQ9NYA1
    ProteomicsDBi83202
    83203 [Q9NYA1-2]

    PTM databases

    iPTMnetiQ9NYA1
    PhosphoSitePlusiQ9NYA1

    Expressioni

    Tissue specificityi

    Widely expressed with highest levels in adult liver, kidney, heart and skeletal muscle.1 Publication

    Gene expression databases

    BgeeiENSG00000176170
    CleanExiHS_SPHK1
    ExpressionAtlasiQ9NYA1 baseline and differential
    GenevisibleiQ9NYA1 HS

    Organism-specific databases

    HPAiHPA022829
    HPA028761

    Interactioni

    Subunit structurei

    Interacts with ACY1 (By similarity). Binds to calmodulin. Interacts with SPHKAP. Interacts with CIB1, the interaction occurs in a calcium-dependent manner.By similarity2 Publications

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    • calmodulin binding Source: UniProtKB
    • protein phosphatase 2A binding Source: BHF-UCL

    Protein-protein interaction databases

    BioGridi114396, 12 interactors
    IntActiQ9NYA1, 56 interactors
    MINTiQ9NYA1
    STRINGi9606.ENSP00000313681

    Chemistry databases

    BindingDBiQ9NYA1

    Structurei

    Secondary structure

    1384
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi13 – 21Combined sources9
    Turni26 – 29Combined sources4
    Helixi30 – 37Combined sources8
    Helixi39 – 44Combined sources6
    Beta strandi47 – 53Combined sources7
    Helixi59 – 66Combined sources8
    Helixi69 – 71Combined sources3
    Beta strandi73 – 80Combined sources8
    Helixi81 – 92Combined sources12
    Helixi97 – 100Combined sources4
    Beta strandi105 – 109Combined sources5
    Helixi115 – 123Combined sources9
    Helixi131 – 144Combined sources14
    Beta strandi146 – 157Combined sources12
    Beta strandi162 – 172Combined sources11
    Helixi173 – 181Combined sources9
    Helixi182 – 190Combined sources9
    Helixi191 – 201Combined sources11
    Beta strandi206 – 214Combined sources9
    Helixi215 – 218Combined sources4
    Beta strandi230 – 232Combined sources3
    Beta strandi249 – 251Combined sources3
    Beta strandi255 – 266Combined sources12
    Beta strandi285 – 291Combined sources7
    Helixi296 – 305Combined sources10
    Helixi306 – 308Combined sources3
    Helixi311 – 314Combined sources4
    Beta strandi319 – 331Combined sources13
    Beta strandi333 – 335Combined sources3
    Beta strandi337 – 340Combined sources4
    Beta strandi343 – 346Combined sources4
    Beta strandi350 – 362Combined sources13

    3D structure databases

    ProteinModelPortaliQ9NYA1
    SMRiQ9NYA1
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini12 – 159DAGKcPROSITE-ProRule annotationAdd BLAST148

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni79 – 82Substrate binding4

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi147 – 155Nuclear export signal 19
    Motifi161 – 169Nuclear export signal 29

    Phylogenomic databases

    eggNOGiKOG1116 Eukaryota
    COG1597 LUCA
    GeneTreeiENSGT00690000101761
    HOGENOMiHOG000111460
    HOVERGENiHBG054796
    InParanoidiQ9NYA1
    KOiK04718
    OMAiLMHEVVN
    OrthoDBiEOG091G06SM
    PhylomeDBiQ9NYA1
    TreeFamiTF354296

    Family and domain databases

    Gene3Di3.40.50.10330, 1 hit
    InterProiView protein in InterPro
    IPR017438 ATP-NAD_kinase_N
    IPR001206 Diacylglycerol_kinase_cat_dom
    IPR016064 NAD/diacylglycerol_kinase_sf
    PfamiView protein in Pfam
    PF00781 DAGK_cat, 1 hit
    SMARTiView protein in SMART
    SM00046 DAGKc, 1 hit
    SUPFAMiSSF111331 SSF111331, 2 hits
    PROSITEiView protein in PROSITE
    PS50146 DAGK, 1 hit

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q9NYA1-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MDPAGGPRGV LPRPCRVLVL LNPRGGKGKA LQLFRSHVQP LLAEAEISFT
    60 70 80 90 100
    LMLTERRNHA RELVRSEELG RWDALVVMSG DGLMHEVVNG LMERPDWETA
    110 120 130 140 150
    IQKPLCSLPA GSGNALAASL NHYAGYEQVT NEDLLTNCTL LLCRRLLSPM
    160 170 180 190 200
    NLLSLHTASG LRLFSVLSLA WGFIADVDLE SEKYRRLGEM RFTLGTFLRL
    210 220 230 240 250
    AALRTYRGRL AYLPVGRVGS KTPASPVVVQ QGPVDAHLVP LEEPVPSHWT
    260 270 280 290 300
    VVPDEDFVLV LALLHSHLGS EMFAAPMGRC AAGVMHLFYV RAGVSRAMLL
    310 320 330 340 350
    RLFLAMEKGR HMEYECPYLV YVPVVAFRLE PKDGKGVFAV DGELMVSEAV
    360 370 380
    QGQVHPNYFW MVSGCVEPPP SWKPQQMPPP EEPL
    Length:384
    Mass (Da):42,518
    Last modified:October 1, 2000 - v1
    Checksum:iEB04A7F2034C2DB0
    GO
    Isoform 2 (identifier: Q9NYA1-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-1: M → MSAQVLGFLR...WQREPRVEVM

    Show »
    Length:470
    Mass (Da):51,054
    Checksum:iF6BF2D324E12CFC0
    GO
    Isoform 3 (identifier: Q9NYA1-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         3-3: P → PVVGCGRGLFGFVFS

    Show »
    Length:398
    Mass (Da):43,944
    Checksum:i7F2C9B26C030E560
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti6Missing in CAB92131 (Ref. 4) Curated1
    Sequence conflicti11 – 15LPRPC → ARL in CAB92131 (Ref. 4) Curated5
    Sequence conflicti114 – 115NA → KP in CAB92131 (Ref. 4) Curated2
    Sequence conflicti251V → M in AAF73423 (PubMed:10802064).Curated1
    Sequence conflicti260V → I in AAF73423 (PubMed:10802064).Curated1
    Sequence conflicti302L → F in AAF73423 (PubMed:10802064).Curated1
    Sequence conflicti325V → G in CAB92131 (Ref. 4) Curated1
    Sequence conflicti337V → M in AAG01980 (PubMed:10947957).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Isoform 2 (identifier: Q9NYA1-2)
    Natural varianti34A → T. Corresponds to variant dbSNP:rs346803Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0354531M → MSAQVLGFLRSWTPLPLAAP RGPAAAGNDAGAPAATAPGG EGEPHSRPCDARLGSTDKEL KAGAAATGSAPTAPGTPWQR EPRVEVM in isoform 2. 2 Publications1
    Alternative sequenceiVSP_0470783P → PVVGCGRGLFGFVFS in isoform 3. 1 Publication1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF266756 mRNA Translation: AAF73470.1
    AF238083 mRNA Translation: AAF73423.1
    AF200328 mRNA Translation: AAG01980.1
    AK023393 mRNA Translation: BAB14558.1
    AK292294 mRNA Translation: BAF84983.1
    AK022402 mRNA Translation: BAB14028.1
    AJ245504 mRNA Translation: CAB92131.1
    AC090699 Genomic DNA No translation available.
    CH471099 Genomic DNA Translation: EAW89392.1
    CH471099 Genomic DNA Translation: EAW89393.1
    BC009419 mRNA Translation: AAH09419.1
    BC014439 mRNA Translation: AAH14439.1
    BC030553 mRNA Translation: AAH30553.1
    CCDSiCCDS11744.1 [Q9NYA1-2]
    CCDS45785.1 [Q9NYA1-1]
    CCDS59297.1 [Q9NYA1-3]
    RefSeqiNP_001136073.1, NM_001142601.1 [Q9NYA1-1]
    NP_001136074.1, NM_001142602.1 [Q9NYA1-1]
    NP_068807.2, NM_021972.3 [Q9NYA1-3]
    NP_892010.2, NM_182965.2 [Q9NYA1-2]
    XP_005257823.1, XM_005257766.2
    UniGeneiHs.68061

    Genome annotation databases

    EnsembliENST00000323374; ENSP00000313681; ENSG00000176170 [Q9NYA1-2]
    ENST00000392496; ENSP00000376285; ENSG00000176170 [Q9NYA1-1]
    ENST00000545180; ENSP00000440970; ENSG00000176170 [Q9NYA1-1]
    ENST00000590959; ENSP00000468547; ENSG00000176170 [Q9NYA1-3]
    ENST00000592299; ENSP00000465726; ENSG00000176170 [Q9NYA1-1]
    GeneIDi8877
    KEGGihsa:8877
    UCSCiuc002jrf.1 human [Q9NYA1-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiSPHK1_HUMAN
    AccessioniPrimary (citable) accession number: Q9NYA1
    Secondary accession number(s): Q8N632
    , Q96GK1, Q9HD92, Q9NY70, Q9NYL3
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 24, 2001
    Last sequence update: October 1, 2000
    Last modified: June 20, 2018
    This is version 160 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 17
      Human chromosome 17: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references

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