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Q9Z2B9

- KS6A4_MOUSE

UniProt

Q9Z2B9 - KS6A4_MOUSE

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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

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 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
Complete GO annotation...

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
Complete GO annotation...

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

MaxQBiQ9Z2B9.
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, 371-717.
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.
GeneTreeiENSGT00760000119016.
HOGENOMiHOG000233033.
HOVERGENiHBG108317.
InParanoidiQ9Z2B9.
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.
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 [UniParc]FASTAAdd to Basket

« Hide

        10         20         30         40         50
MGDEDEDEGC AVELQITEAN LTGHEEKVSV ENFALLKVLG TGAYGKVFLV
60 70 80 90 100
RKTGGHDAGK LYAMKVLRKA ALVQRAKTQE HTRTERSVLE LVRQAPFLVT
110 120 130 140 150
LHYAFQTDAK LHLILDYVSG GEMFTHLYQR QYFKEAEVRV YGGEIVLALE
160 170 180 190 200
HLHKLGIIYR DLKLENVLLD SEGHIVLTDF GLSKEFLTEE KERTFSFCGT
210 220 230 240 250
IEYMAPEIIR SKAGHGKAVD WWSLGILLFE LLTGASPFTL EGERNTQAEV
260 270 280 290 300
SRRILKCSPP FPLRIGPVAQ DLLQRLLCKD PKKRLGAGPQ GAQEVKSHPF
310 320 330 340 350
FQGLDWVALA ARKIPAPFRP QIRSELDVGN FAEEFTRLEP VYSPAGSPPP
360 370 380 390 400
GDPRIFQGYS FVAPSILFDH NNAVMADVLQ APGAGYRPGR AAVARSAMMQ
410 420 430 440 450
DSPFFQQYEL DLREPALGQG SFSVCRRCRQ RQSGQEFAVK ILSRRLEENT
460 470 480 490 500
QREVAALRLC QSHPNVVNLH EVLHDQLHTY LVLELLRGGE LLEHIRKKRL
510 520 530 540 550
FSESEASQIL RSLVSAVSFM HEEAGVVHRD LKPENILYAD DTPGAPVKII
560 570 580 590 600
DFGFARLRPQ SPAEPMQTPC FTLQYAAPEL LAQQGYDESC DLWSLGVILY
610 620 630 640 650
MMLSGQVPFQ GASGQGGQSQ AAEIMCKIRE GRFSLDGEAW QGVSEEAKEL
660 670 680 690 700
VRGLLTVDPA KRLKLEGLRS SSWLQDGSAR SSPPLRTPDV LESSGPAVRS
710 720 730 740 750
GLNATFMAFN RGKREGFFLK SVENAPLAKR RKQKLRSAAA SRRGSPVPAS
760 770
SGRLPASAAK GTTRRANGPL SPS
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, 371-717.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

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

PTM databases

PhosphoSitei Q9Z2B9.

Proteomic databases

MaxQBi Q9Z2B9.
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 ENSGT00760000119016.
HOGENOMi HOG000233033.
HOVERGENi HBG108317.
InParanoidi Q9Z2B9.
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.
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

« Hide 'large scale' publications
  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 29, 2014
This is version 130 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