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Q9Z2B9

- KS6A4_MOUSE

UniProt

Q9Z2B9 - KS6A4_MOUSE

Protein

Ribosomal protein S6 kinase alpha-4

Gene

Rps6ka4

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 129 (01 Oct 2014)
      Sequence version 2 (27 Jul 2011)
      Previous versions | rss
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    Functioni

    Serine/threonine-protein kinase that is required for the mitogen or stress-induced phosphorylation of the transcription factors CREB1 and ATF1 and for the regulation of the transcription factor RELA, and that contributes to gene activation by histone phosphorylation and functions in the regulation of inflammatory genes. Phosphorylates CREB1 and ATF1 in response to mitogenic or stress stimuli such as UV-C irradiation, epidermal growth factor (EGF) and anisomycin. Plays an essential role in the control of RELA transcriptional activity in response to TNF. Phosphorylates 'Ser-10' of histone H3 in response to mitogenics, stress stimuli and EGF, which results in the transcriptional activation of several immediate early genes, including proto-oncogenes c-fos/FOS and c-jun/JUN. May also phosphorylate 'Ser-28' of histone H3. Mediates the mitogen- and stress-induced phosphorylation of high mobility group protein 1 (HMGN1/HMG14). In lipopolysaccharide-stimulated primary macrophages, acts downstream of the Toll-like receptor TLR4 to limit the production of pro-inflammatory cytokines. Functions probably by inducing transcription of the MAP kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10 (IL10), via CREB1 and ATF1 transcription factors By similarity.By similarity

    Catalytic activityi

    ATP + a protein = ADP + a phosphoprotein.By similarity

    Cofactori

    Magnesium.By similarity

    Enzyme regulationi

    Activated by phosphorylation at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-196, Ser-360 and Ser-365 by the activated C-terminal kinase domain.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei65 – 651ATPPROSITE-ProRule annotation
    Active sitei161 – 1611Proton acceptorBy similarity
    Binding sitei440 – 4401ATPPROSITE-ProRule annotation
    Active sitei530 – 5301Proton acceptorBy similarity

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi39 – 479ATPPROSITE-ProRule annotation
    Nucleotide bindingi417 – 4259ATPPROSITE-ProRule annotation

    GO - Molecular functioni

    1. ATP binding Source: UniProtKB
    2. magnesium ion binding Source: InterPro
    3. mitogen-activated protein kinase p38 binding Source: UniProtKB
    4. protein binding Source: IntAct
    5. protein serine/threonine kinase activity Source: UniProtKB

    GO - Biological processi

    1. histone H3-S10 phosphorylation Source: UniProtKB
    2. histone H3-S28 phosphorylation Source: UniProtKB
    3. inflammatory response Source: UniProtKB-KW
    4. interleukin-1-mediated signaling pathway Source: Ensembl
    5. intracellular signal transduction Source: UniProtKB
    6. positive regulation of histone acetylation Source: Ensembl
    7. positive regulation of histone phosphorylation Source: Ensembl
    8. positive regulation of transcription from RNA polymerase II promoter Source: Ensembl
    9. protein phosphorylation Source: UniProtKB
    10. regulation of transcription, DNA-templated Source: UniProtKB

    Keywords - Molecular functioni

    Kinase, Serine/threonine-protein kinase, Transferase

    Keywords - Biological processi

    Inflammatory response, Stress response

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Ribosomal protein S6 kinase alpha-4 (EC:2.7.11.1)
    Short name:
    S6K-alpha-4
    Alternative name(s):
    90 kDa ribosomal protein S6 kinase 4
    Nuclear mitogen- and stress-activated protein kinase 2
    RSK-like protein kinase
    Short name:
    RLSK
    Gene namesi
    Name:Rps6ka4
    Synonyms:Msk2
    OrganismiMus musculus (Mouse)Imported
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 19

    Organism-specific databases

    MGIiMGI:1930076. Rps6ka4.

    Subcellular locationi

    Nucleus By similarity

    GO - Cellular componenti

    1. cytoplasm Source: Ensembl
    2. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 773773Ribosomal protein S6 kinase alpha-4PRO_0000086206Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei196 – 1961Phosphoserine; by autocatalysisBy similarity
    Modified residuei343 – 3431Phosphoserine; by MAPK1, MAPK3 and MAPK14Curated
    Modified residuei347 – 3471PhosphoserineBy similarity
    Modified residuei360 – 3601Phosphoserine; by autocatalysisBy similarity
    Modified residuei365 – 3651Phosphoserine; by autocatalysisBy similarity
    Modified residuei542 – 5421PhosphothreonineBy similarity
    Modified residuei568 – 5681Phosphothreonine; by MAPK1, MAPK3 and MAPK14By similarity
    Modified residuei634 – 6341PhosphoserineBy similarity
    Modified residuei678 – 6781PhosphoserineBy similarity
    Modified residuei687 – 6871Phosphothreonine; by MAPK1, MAPK3 and MAPK14By similarity
    Modified residuei737 – 7371Phosphoserine; by autocatalysisBy similarity
    Modified residuei745 – 7451Phosphoserine; by autocatalysisCurated

    Post-translational modificationi

    Ser-343 and Thr-568 phosphorylation is required for kinase activity. Ser-343 and Ser-196 are autophosphorylated by the C-terminal kinase domain, and their phosphorylation is essential for the catalytic activity of the N-terminal kinase domain. Phosphorylated at Ser-343, Thr-568 and Thr-687 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-737 and Ser-745 by the N-terminal kinase domain By similarity.By similarity

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    PaxDbiQ9Z2B9.
    PRIDEiQ9Z2B9.

    PTM databases

    PhosphoSiteiQ9Z2B9.

    Expressioni

    Gene expression databases

    BgeeiQ9Z2B9.
    CleanExiMM_RPS6KA4.
    GenevestigatoriQ9Z2B9.

    Interactioni

    Subunit structurei

    Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells which transiently dissociates following mitogenic stimulation. Also associates with MAPK14/p38-alpha. Activated RPS6KA4 associates with and phosphorylates the NF-kappa-B p65 subunit RELA By similarity.By similarity

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Mapk1P630853EBI-412887,EBI-397697

    Protein-protein interaction databases

    BioGridi208103. 1 interaction.
    IntActiQ9Z2B9. 1 interaction.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9Z2B9.
    SMRiQ9Z2B9. Positions 12-365, 373-717.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini33 – 301269Protein kinase 1PROSITE-ProRule annotationAdd
    BLAST
    Domaini302 – 37170AGC-kinase C-terminalAdd
    BLAST
    Domaini417 – 674258Protein kinase 2PROSITE-ProRule annotationAdd
    BLAST

    Sequence similaritiesi

    Contains 1 AGC-kinase C-terminal domain.Curated
    Contains 2 protein kinase domains.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiCOG0515.
    GeneTreeiENSGT00730000110260.
    HOGENOMiHOG000233033.
    HOVERGENiHBG108317.
    InParanoidiQ3U3M8.
    KOiK16510.
    OMAiYHTYLVM.
    OrthoDBiEOG76HQ0Z.
    TreeFamiTF313438.

    Family and domain databases

    InterProiIPR000961. AGC-kinase_C.
    IPR011009. Kinase-like_dom.
    IPR017892. Pkinase_C.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR016239. Ribosomal_S6_kinase_II.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view]
    PfamiPF00069. Pkinase. 2 hits.
    PF00433. Pkinase_C. 1 hit.
    [Graphical view]
    PIRSFiPIRSF000606. Ribsml_S6_kin_2. 1 hit.
    SMARTiSM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 2 hits.
    [Graphical view]
    SUPFAMiSSF56112. SSF56112. 2 hits.
    PROSITEiPS51285. AGC_KINASE_CTER. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 2 hits.
    PS50011. PROTEIN_KINASE_DOM. 2 hits.
    PS00108. PROTEIN_KINASE_ST. 2 hits.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q9Z2B9-1 [UniParc]FASTAAdd to Basket

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    MGDEDEDEGC AVELQITEAN LTGHEEKVSV ENFALLKVLG TGAYGKVFLV    50
    RKTGGHDAGK LYAMKVLRKA ALVQRAKTQE HTRTERSVLE LVRQAPFLVT 100
    LHYAFQTDAK LHLILDYVSG GEMFTHLYQR QYFKEAEVRV YGGEIVLALE 150
    HLHKLGIIYR DLKLENVLLD SEGHIVLTDF GLSKEFLTEE KERTFSFCGT 200
    IEYMAPEIIR SKAGHGKAVD WWSLGILLFE LLTGASPFTL EGERNTQAEV 250
    SRRILKCSPP FPLRIGPVAQ DLLQRLLCKD PKKRLGAGPQ GAQEVKSHPF 300
    FQGLDWVALA ARKIPAPFRP QIRSELDVGN FAEEFTRLEP VYSPAGSPPP 350
    GDPRIFQGYS FVAPSILFDH NNAVMADVLQ APGAGYRPGR AAVARSAMMQ 400
    DSPFFQQYEL DLREPALGQG SFSVCRRCRQ RQSGQEFAVK ILSRRLEENT 450
    QREVAALRLC QSHPNVVNLH EVLHDQLHTY LVLELLRGGE LLEHIRKKRL 500
    FSESEASQIL RSLVSAVSFM HEEAGVVHRD LKPENILYAD DTPGAPVKII 550
    DFGFARLRPQ SPAEPMQTPC FTLQYAAPEL LAQQGYDESC DLWSLGVILY 600
    MMLSGQVPFQ GASGQGGQSQ AAEIMCKIRE GRFSLDGEAW QGVSEEAKEL 650
    VRGLLTVDPA KRLKLEGLRS SSWLQDGSAR SSPPLRTPDV LESSGPAVRS 700
    GLNATFMAFN RGKREGFFLK SVENAPLAKR RKQKLRSAAA SRRGSPVPAS 750
    SGRLPASAAK GTTRRANGPL SPS 773
    Length:773
    Mass (Da):85,652
    Last modified:July 27, 2011 - v2
    Checksum:i298DA76E00A9937F
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti307 – 3071V → W in AAC67394. (PubMed:9687510)Curated
    Sequence conflicti343 – 3431S → P in AAH12964. (PubMed:15489334)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF074714 mRNA. Translation: AAC67394.1.
    AK154674 mRNA. Translation: BAE32757.1.
    BC012964 mRNA. Translation: AAH12964.1.
    CCDSiCCDS37899.1.
    RefSeqiNP_064308.2. NM_019924.2.
    XP_006527294.1. XM_006527231.1.
    UniGeneiMm.20914.

    Genome annotation databases

    EnsembliENSMUST00000025903; ENSMUSP00000025903; ENSMUSG00000024952.
    ENSMUST00000170516; ENSMUSP00000131581; ENSMUSG00000024952.
    GeneIDi56613.
    KEGGimmu:56613.
    UCSCiuc008gja.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF074714 mRNA. Translation: AAC67394.1 .
    AK154674 mRNA. Translation: BAE32757.1 .
    BC012964 mRNA. Translation: AAH12964.1 .
    CCDSi CCDS37899.1.
    RefSeqi NP_064308.2. NM_019924.2.
    XP_006527294.1. XM_006527231.1.
    UniGenei Mm.20914.

    3D structure databases

    ProteinModelPortali Q9Z2B9.
    SMRi Q9Z2B9. Positions 12-365, 373-717.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 208103. 1 interaction.
    IntActi Q9Z2B9. 1 interaction.

    PTM databases

    PhosphoSitei Q9Z2B9.

    Proteomic databases

    PaxDbi Q9Z2B9.
    PRIDEi Q9Z2B9.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000025903 ; ENSMUSP00000025903 ; ENSMUSG00000024952 .
    ENSMUST00000170516 ; ENSMUSP00000131581 ; ENSMUSG00000024952 .
    GeneIDi 56613.
    KEGGi mmu:56613.
    UCSCi uc008gja.1. mouse.

    Organism-specific databases

    CTDi 8986.
    MGIi MGI:1930076. Rps6ka4.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00730000110260.
    HOGENOMi HOG000233033.
    HOVERGENi HBG108317.
    InParanoidi Q3U3M8.
    KOi K16510.
    OMAi YHTYLVM.
    OrthoDBi EOG76HQ0Z.
    TreeFami TF313438.

    Miscellaneous databases

    NextBioi 313035.
    PROi Q9Z2B9.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q9Z2B9.
    CleanExi MM_RPS6KA4.
    Genevestigatori Q9Z2B9.

    Family and domain databases

    InterProi IPR000961. AGC-kinase_C.
    IPR011009. Kinase-like_dom.
    IPR017892. Pkinase_C.
    IPR000719. Prot_kinase_dom.
    IPR017441. Protein_kinase_ATP_BS.
    IPR016239. Ribosomal_S6_kinase_II.
    IPR002290. Ser/Thr_dual-sp_kinase_dom.
    IPR008271. Ser/Thr_kinase_AS.
    [Graphical view ]
    Pfami PF00069. Pkinase. 2 hits.
    PF00433. Pkinase_C. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF000606. Ribsml_S6_kin_2. 1 hit.
    SMARTi SM00133. S_TK_X. 1 hit.
    SM00220. S_TKc. 2 hits.
    [Graphical view ]
    SUPFAMi SSF56112. SSF56112. 2 hits.
    PROSITEi PS51285. AGC_KINASE_CTER. 1 hit.
    PS00107. PROTEIN_KINASE_ATP. 2 hits.
    PS50011. PROTEIN_KINASE_DOM. 2 hits.
    PS00108. PROTEIN_KINASE_ST. 2 hits.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB."
      Deak M., Clifton A.D., Lucocq J.M., Alessi D.R.
      EMBO J. 17:4426-4441(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    2. "The transcriptional landscape of the mammalian genome."
      Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
      , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
      Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: NOD.
    3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: LiverImported.
    4. "MSK1 and MSK2 are required for the mitogen- and stress-induced phosphorylation of CREB and ATF1 in fibroblasts."
      Wiggin G.R., Soloaga A., Foster J.M., Murray-Tait V., Cohen P., Arthur J.S.
      Mol. Cell. Biol. 22:2871-2881(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1 AND ATF1.
    5. "The kinases MSK1 and MSK2 are required for epidermal growth factor-induced, but not tumor necrosis factor-induced, histone H3 Ser10 phosphorylation."
      Duncan E.A., Anest V., Cogswell P., Baldwin A.S.
      J. Biol. Chem. 281:12521-12525(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF HISTONE H3.
    6. "The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling."
      Ananieva O., Darragh J., Johansen C., Carr J.M., McIlrath J., Park J.M., Wingate A., Monk C.E., Toth R., Santos S.G., Iversen L., Arthur J.S.
      Nat. Immunol. 9:1028-1036(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN PHOSPHORYLATION OF CREB1; ATF1 AND HISTONE H3.

    Entry informationi

    Entry nameiKS6A4_MOUSE
    AccessioniPrimary (citable) accession number: Q9Z2B9
    Secondary accession number(s): Q3U3M8, Q91X18
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 24, 2003
    Last sequence update: July 27, 2011
    Last modified: October 1, 2014
    This is version 129 of the entry and version 2 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Miscellaneous

    Enzyme activity requires the presence of both kinase domains.By similarity

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3