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P18654 (KS6A3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 147. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ribosomal protein S6 kinase alpha-3

Short name=S6K-alpha-3
EC=2.7.11.1
Alternative name(s):
90 kDa ribosomal protein S6 kinase 3
Short name=p90-RSK 3
Short name=p90RSK3
MAP kinase-activated protein kinase 1b
Short name=MAPK-activated protein kinase 1b
Short name=MAPKAP kinase 1b
Short name=MAPKAPK-1b
Ribosomal S6 kinase 2
Short name=RSK-2
pp90RSK2
Gene names
Name:Rps6ka3
Synonyms:Mapkapk1b, Rps6ka-rs1, Rsk2
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length740 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of the transcription factors CREB1, ETV1/ER81 and NR4A1/NUR77, regulates translation through RPS6 and EIF4B phosphorylation, and mediates cellular proliferation, survival, and differentiation by modulating mTOR signaling and repressing pro-apoptotic function of BAD and DAPK1. In fibroblast, is required for EGF-stimulated phosphorylation of CREB1 and histone H3 at 'Ser-10', which results in the subsequent transcriptional activation of several immediate-early genes. In response to mitogenic stimulation (EGF and PMA), phosphorylates and activates NR4A1/NUR77 and ETV1/ER81 transcription factors and the cofactor CREBBP. Upon insulin-derived signal, acts indirectly on the transcription regulation of several genes by phosphorylating GSK3B at 'Ser-9' and inhibiting its activity. Phosphorylates RPS6 in response to serum or EGF via an mTOR-independent mechanism and promotes translation initiation by facilitating assembly of the preinitiation complex. In response to insulin, phosphorylates EIF4B, enhancing EIF4B affinity for the EIF3 complex and stimulating cap-dependent translation. Is involved in the mTOR nutrient-sensing pathway by directly phosphorylating TSC2 at 'Ser-1798', which potently inhibits TSC2 ability to suppress mTOR signaling, and mediates phosphorylation of RPTOR, which regulates mTORC1 activity and may promote rapamycin-sensitive signaling independently of the PI3K/AKT pathway. Mediates cell survival by phosphorylating the pro-apoptotic proteins BAD and DAPK1 and suppressing their pro-apoptotic function. Promotes the survival of hepatic stellate cells by phosphorylating CEBPB in response to the hepatotoxin carbon tetrachloride (CCl4). Is involved in cell cycle regulation by phosphorylating the CDK inhibitor CDKN1B, which promotes CDKN1B association with 14-3-3 proteins and prevents its translocation to the nucleus and inhibition of G1 progression. In LPS-stimulated dendritic cells, is involved in TLR4-induced macropinocytosis, and in myeloma cells, acts as effector of FGFR3-mediated transformation signaling, after direct phosphorylation at Tyr-529 by FGFR3. Phosphorylates DAPK1 By similarity. Ref.5 Ref.6 Ref.7 Ref.8

Catalytic activity

ATP + a protein = ADP + a phosphoprotein.

Cofactor

Magnesium By similarity.

Enzyme regulation

Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-577 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-386, allowing binding of PDPK1, which in turn phosphorylates Ser-227 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD By similarity. Ref.4 Ref.5

Subunit structure

Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation By similarity. Interacts with NFATC4, ETV1/ER81 and FGFR1 By similarity.

Subcellular location

Nucleus By similarity. Cytoplasm By similarity.

Tissue specificity

Intestine, thymus, lung, heart and brain.

Post-translational modification

Activated by phosphorylation at Ser-227 by PDPK1. Autophosphorylated on Ser-386, as part of the activation process. May be phosphorylated at Thr-365 and Ser-369 by MAPK1/ERK2 and MAPK3/ERK1. Can also be activated via phosphorylation at Ser-386 by MAPKAPK2. Ref.4 Ref.7 Ref.8

N-terminal myristoylation results in an activated kinase in the absence of added growth factors By similarity.

Sequence similarities

Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. S6 kinase subfamily.

Contains 1 AGC-kinase C-terminal domain.

Contains 2 protein kinase domains.

Ontologies

Keywords
   Biological processCell cycle
Stress response
   Cellular componentCytoplasm
Nucleus
   DomainRepeat
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Serine/threonine-protein kinase
Transferase
   PTMPhosphoprotein
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell cycle

Inferred from electronic annotation. Source: UniProtKB-KW

intracellular signal transduction

Inferred from electronic annotation. Source: InterPro

positive regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

response to lipopolysaccharide

Inferred from mutant phenotype Ref.8. Source: UniProtKB

response to stress

Inferred from electronic annotation. Source: UniProtKB-KW

toll-like receptor signaling pathway

Inferred from mutant phenotype Ref.8. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cysteine-type endopeptidase inhibitor activity involved in apoptotic process

Inferred from electronic annotation. Source: Ensembl

magnesium ion binding

Inferred from electronic annotation. Source: InterPro

protein kinase binding

Inferred from physical interaction Ref.8. Source: UniProtKB

protein serine/threonine kinase activity

Inferred from direct assay Ref.1. Source: MGI

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 740740Ribosomal protein S6 kinase alpha-3
PRO_0000086204

Regions

Domain68 – 327260Protein kinase 1
Domain328 – 39770AGC-kinase C-terminal
Domain422 – 679258Protein kinase 2
Nucleotide binding74 – 829ATP By similarity
Nucleotide binding428 – 4369ATP By similarity

Sites

Active site1931Proton acceptor By similarity
Active site5391Proton acceptor By similarity
Binding site1001ATP By similarity
Binding site4511ATP By similarity

Amino acid modifications

Modified residue2271Phosphoserine; by PDPK1 Ref.4
Modified residue3651Phosphothreonine By similarity
Modified residue3691Phosphoserine By similarity
Modified residue3751Phosphoserine By similarity
Modified residue3861Phosphoserine; by autocatalysis and MAPKAPK2 Ref.4 Ref.8
Modified residue4151Phosphoserine By similarity
Modified residue5291Phosphotyrosine; by FGFR3 Ref.7
Modified residue5561Phosphoserine By similarity
Modified residue7151Phosphoserine By similarity

Experimental info

Mutagenesis2271S → E: Loss of phosphorylation and activation by PDPK1. Ref.4
Mutagenesis3861S → A: Loss of phosphorylation by PDPK1; loss of activation by PDPK1 and EGF. Ref.4 Ref.5
Mutagenesis3861S → E: Loss of interaction with PDPK1 and phosphorylation at S-227. Ref.4 Ref.5
Mutagenesis5291Y → F: Attenuates activation by MAPK1/ERK1 and MAPK3/ERK2. Ref.7

Secondary structure

............................................................................................ 740
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P18654 [UniParc].

Last modified March 25, 2003. Version 2.
Checksum: 0CD54E5918567007

FASTA74083,694
        10         20         30         40         50         60 
MPLAQLADPW QKMAVESPSD SAENGQQIMD EPMGEEEINP QTEEGSIKEI AITHHVKEGH 

        70         80         90        100        110        120 
EKADPSQFEL LKVLGQGSFG KVFLVKKISG SDARQLYAMK VLKKATLKVR DRVRTKMERD 

       130        140        150        160        170        180 
ILVEVNHPFI VKLHYAFQTE GKLYLILDFL RGGDLFTRLS KEVMFTEEDV KFYLAELALA 

       190        200        210        220        230        240 
LDHLHSLGII YRDLKPENIL LDEEGHIKLT DFGLSKESID HEKKAYSFCG TVEYMAPEVV 

       250        260        270        280        290        300 
NRRGHTQSAD WWSFGVLMFE MLTGTLPFQG KDRKETMTMI LKAKLGMPQF LSPEAQSLLR 

       310        320        330        340        350        360 
MLFKRNPANR LGAGPDGVEE IKRHSFFSTI DWNKLYRREI HPPFKPATGR PEDTFYFDPE 

       370        380        390        400        410        420 
FTAKTPKDSP GIPPSANAHQ LFRGFSFVAI TSDDESQAMQ TVGVHSIVQQ LHRNSIQFTD 

       430        440        450        460        470        480 
GYEVKEDIGV GSYSVCKRCI HKATNMEFAV KIIDKSKRDP TEEIEILLRY GQHPNIITLK 

       490        500        510        520        530        540 
DVYDDGKYVY VVTELMKGGE LLDKILRQKF FSEREASAVL FTITKTVEYL HAQGVVHRDL 

       550        560        570        580        590        600 
KPSNILYVDE SGNPESIRIC DFGFAKQLRA ENGLLMTPCY TANFVAPEVL KRQGYDAACD 

       610        620        630        640        650        660 
IWSLGVLLYT MLTGYTPFAN GPDDTPEEIL ARIGSGKFSL SGGYWNSVSD TAKDLVSKML 

       670        680        690        700        710        720 
HVDPHQRLTA ALVLRHPWIV HWDQLPQYQL NRQDAPHLVK GAMAATYSAL NRNQSPVLEP 

       730        740 
VGRSTLAQRR GIKKITSTAL 

« Hide

References

« Hide 'large scale' references
[1]"Characterization of the p90 ribosomal S6 kinase 2 carboxyl-terminal domain as a protein kinase."
Chrestensen C.A., Sturgill T.W.
J. Biol. Chem. 277:27733-27741(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[3]"Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase."
Alcorta D.A., Crews C.M., Sweet L.J., Bankston L., Jones S.W., Erikson R.L.
Mol. Cell. Biol. 9:3850-3859(1989) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 108-740.
[4]"90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1."
Jensen C.J., Buch M.-B., Krag T.O., Hemmings B.A., Gammeltoft S., Froedin M.
J. Biol. Chem. 274:27168-27176(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-227 AND SER-386, MUTAGENESIS OF SER-227 AND SER-386.
[5]"A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1."
Froedin M., Jensen C.J., Merienne K., Gammeltoft S.
EMBO J. 19:2924-2934(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, MUTAGENESIS OF SER-386.
[6]"Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization."
Fujita N., Sato S., Tsuruo T.
J. Biol. Chem. 278:49254-49260(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF CDKN1B.
[7]"FGFR3 activates RSK2 to mediate hematopoietic transformation through tyrosine phosphorylation of RSK2 and activation of the MEK/ERK pathway."
Kang S., Dong S., Gu T.L., Guo A., Cohen M.S., Lonial S., Khoury H.J., Fabbro D., Gilliland D.G., Bergsagel P.L., Taunton J., Polakiewicz R.D., Chen J.
Cancer Cell 12:201-214(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN HEMATOPOIETIC TRANSFORMATION, PHOSPHORYLATION AT TYR-529, MUTAGENESIS OF TYR-529.
[8]"The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways."
Zaru R., Ronkina N., Gaestel M., Arthur J.S., Watts C.
Nat. Immunol. 8:1227-1235(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN TOLL-LIKE RECEPTOR SIGNALING, PHOSPHORYLATION AT SER-386.
[9]"Structural basis for activation of the autoinhibitory C-terminal kinase domain of p90 RSK2."
Malakhova M., Tereshko V., Lee S.Y., Yao K., Cho Y.Y., Bode A., Dong Z.
Nat. Struct. Mol. Biol. 15:112-113(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 399-740.
[10]"Structural diversity of the active N-terminal kinase domain of p90 ribosomal S6 kinase 2."
Malakhova M., Kurinov I., Liu K., Zheng D., D'Angelo I., Shim J.H., Steinman V., Bode A.M., Dong Z.
PLoS ONE 4:E8044-E8044(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 44-367.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY083469 mRNA. Translation: AAM00022.1.
AL808146 Genomic DNA. Translation: CAM25836.1.
CCDSCCDS30502.1.
PIRC32571.
S30504.
RefSeqNP_683747.1. NM_148945.2.
UniGeneMm.328476.
Mm.392829.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2QR7X-ray2.00A399-740[»]
2QR8X-ray2.00A399-740[»]
3G51X-ray1.80A44-367[»]
3UBDX-ray1.53A45-346[»]
4EL9X-ray1.55A45-346[»]
4GUEX-ray1.80A45-346[»]
ProteinModelPortalP18654.
SMRP18654. Positions 51-714.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid225783. 6 interactions.
DIPDIP-31554N.
IntActP18654. 7 interactions.
MINTMINT-1486771.

Chemistry

BindingDBP18654.

PTM databases

PhosphoSiteP18654.

Proteomic databases

MaxQBP18654.
PaxDbP18654.
PRIDEP18654.

Protocols and materials databases

DNASU110651.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000033671; ENSMUSP00000033671; ENSMUSG00000031309.
GeneID110651.
KEGGmmu:110651.
UCSCuc009usj.1. mouse.

Organism-specific databases

CTD6197.
MGIMGI:104557. Rps6ka3.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00730000110260.
HOVERGENHBG108317.
InParanoidB1AXN4.
KOK04373.
OMAHPWIVHC.
PhylomeDBP18654.
TreeFamTF313438.

Gene expression databases

ArrayExpressP18654.
BgeeP18654.
CleanExMM_RPS6KA3.
GenevestigatorP18654.

Family and domain databases

InterProIPR000961. 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]
PfamPF00069. Pkinase. 2 hits.
PF00433. Pkinase_C. 1 hit.
[Graphical view]
PIRSFPIRSF000606. Ribsml_S6_kin_2. 1 hit.
SMARTSM00133. S_TK_X. 1 hit.
SM00220. S_TKc. 2 hits.
[Graphical view]
SUPFAMSSF56112. SSF56112. 2 hits.
PROSITEPS51285. 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]
ProtoNetSearch...

Other

ChiTaRSRPS6KA3. mouse.
EvolutionaryTraceP18654.
NextBio364399.
PROP18654.
SOURCESearch...

Entry information

Entry nameKS6A3_MOUSE
AccessionPrimary (citable) accession number: P18654
Secondary accession number(s): B1AXN4, Q03140, Q8K3J8
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: March 25, 2003
Last modified: July 9, 2014
This is version 147 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot