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Protein

Ribosomal protein S6 kinase alpha-3

Gene

Rps6ka3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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). Negatively regulates EGF-induced MAPK1/3 phosphorylation via phosphorylation of SOS1. Phosphorylates SOS1 at 'Ser-1134' and 'Ser-1161' that create YWHAB and YWHAE binding sites and which contribute to the negative regulation of MAPK1/3 phosphorylation (PubMed:22827337). Phosphorylates EPHA2 at 'Ser-897',the RPS6KA-EPHA2 signaling pathway controls cell migration (By similarity).By similarity5 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+By similarity

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei100ATPPROSITE-ProRule annotation1
Active sitei193Proton acceptorBy similarity1
Binding sitei451ATPPROSITE-ProRule annotation1
Active sitei539Proton acceptorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi74 – 82ATPPROSITE-ProRule annotation9
Nucleotide bindingi428 – 436ATPPROSITE-ProRule annotation9

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Cell cycle, Stress response

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-198753. ERK/MAPK targets.
R-MMU-199920. CREB phosphorylation.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-442742. CREB phosphorylation through the activation of Ras.
R-MMU-444257. RSK activation.
R-MMU-881907. Gastrin-CREB signalling pathway via PKC and MAPK.

Names & Taxonomyi

Protein namesi
Recommended name:
Ribosomal protein S6 kinase alpha-3 (EC:2.7.11.1)
Short name:
S6K-alpha-3
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 namesi
Name:Rps6ka3
Synonyms:Mapkapk1b, Rps6ka-rs1, Rsk2
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome X

Organism-specific databases

MGIiMGI:104557. Rps6ka3.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi227S → E: Loss of phosphorylation and activation by PDPK1. 1 Publication1
Mutagenesisi386S → A: Loss of phosphorylation by PDPK1; loss of activation by PDPK1 and EGF. 2 Publications1
Mutagenesisi386S → E: Loss of interaction with PDPK1 and phosphorylation at S-227. 2 Publications1
Mutagenesisi529Y → F: Attenuates activation by MAPK1/ERK1 and MAPK3/ERK2. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL3297641.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862041 – 740Ribosomal protein S6 kinase alpha-3Add BLAST740

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei227Phosphoserine; by PDPK11 Publication1
Modified residuei365PhosphothreonineCombined sources1
Modified residuei369PhosphoserineCombined sources1
Modified residuei375PhosphoserineBy similarity1
Modified residuei386Phosphoserine; by autocatalysis and MAPKAPK22 Publications1
Modified residuei415PhosphoserineCombined sources1
Modified residuei529Phosphotyrosine; by FGFR31 Publication1
Modified residuei556PhosphoserineBy similarity1
Modified residuei715PhosphoserineCombined sources1

Post-translational modificationi

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 MAPKAPK2.3 Publications
N-terminal myristoylation results in an activated kinase in the absence of added growth factors.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP18654.
MaxQBiP18654.
PaxDbiP18654.
PeptideAtlasiP18654.
PRIDEiP18654.

PTM databases

iPTMnetiP18654.
PhosphoSitePlusiP18654.
SwissPalmiP18654.

Expressioni

Tissue specificityi

Intestine, thymus, lung, heart and brain.

Gene expression databases

BgeeiENSMUSG00000031309.
CleanExiMM_RPS6KA3.
ExpressionAtlasiP18654. baseline and differential.
GenevisibleiP18654. MM.

Interactioni

Subunit structurei

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).By similarity

GO - Molecular functioni

  • protein kinase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi225783. 10 interactors.
DIPiDIP-31554N.
IntActiP18654. 7 interactors.
MINTiMINT-1486771.
STRINGi10090.ENSMUSP00000033671.

Structurei

Secondary structure

1740
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi50 – 56Combined sources7
Helixi65 – 67Combined sources3
Beta strandi68 – 75Combined sources8
Helixi77 – 79Combined sources3
Beta strandi81 – 87Combined sources7
Turni91 – 94Combined sources4
Beta strandi96 – 111Combined sources16
Helixi121 – 124Combined sources4
Beta strandi133 – 139Combined sources7
Beta strandi142 – 147Combined sources6
Helixi156 – 162Combined sources7
Helixi167 – 186Combined sources20
Helixi196 – 198Combined sources3
Beta strandi199 – 201Combined sources3
Beta strandi207 – 216Combined sources10
Helixi232 – 234Combined sources3
Helixi237 – 241Combined sources5
Helixi248 – 263Combined sources16
Helixi273 – 282Combined sources10
Helixi293 – 302Combined sources10
Helixi307 – 309Combined sources3
Turni315 – 317Combined sources3
Helixi318 – 322Combined sources5
Helixi325 – 327Combined sources3
Helixi332 – 336Combined sources5
Helixi418 – 421Combined sources4
Beta strandi422 – 430Combined sources9
Beta strandi432 – 441Combined sources10
Turni442 – 444Combined sources3
Beta strandi447 – 454Combined sources8
Turni455 – 457Combined sources3
Helixi461 – 470Combined sources10
Beta strandi479 – 484Combined sources6
Beta strandi486 – 493Combined sources8
Beta strandi498 – 500Combined sources3
Helixi501 – 506Combined sources6
Helixi513 – 532Combined sources20
Helixi542 – 544Combined sources3
Beta strandi545 – 551Combined sources7
Helixi554 – 556Combined sources3
Beta strandi557 – 559Combined sources3
Helixi562 – 564Combined sources3
Helixi587 – 613Combined sources27
Beta strandi614 – 616Combined sources3
Beta strandi619 – 621Combined sources3
Helixi626 – 635Combined sources10
Turni643 – 647Combined sources5
Helixi650 – 659Combined sources10
Turni664 – 666Combined sources3
Helixi670 – 673Combined sources4
Helixi677 – 680Combined sources4
Helixi682 – 684Combined sources3
Helixi696 – 710Combined sources15
Turni711 – 713Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
4M8TX-ray3.00A399-740[»]
4MAOX-ray2.60A399-740[»]
ProteinModelPortaliP18654.
SMRiP18654.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP18654.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini68 – 327Protein kinase 1PROSITE-ProRule annotationAdd BLAST260
Domaini328 – 397AGC-kinase C-terminalAdd BLAST70
Domaini422 – 679Protein kinase 2PROSITE-ProRule annotationAdd BLAST258

Sequence similaritiesi

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

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0598. Eukaryota.
ENOG410XNPH. LUCA.
GeneTreeiENSGT00860000133668.
HOVERGENiHBG108317.
InParanoidiP18654.
KOiK04373.
OMAiYTLNRQD.
OrthoDBiEOG091G05Z7.
PhylomeDBiP18654.
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.
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.

P18654-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPLAQLADPW QKMAVESPSD SAENGQQIMD EPMGEEEINP QTEEGSIKEI
60 70 80 90 100
AITHHVKEGH EKADPSQFEL LKVLGQGSFG KVFLVKKISG SDARQLYAMK
110 120 130 140 150
VLKKATLKVR DRVRTKMERD ILVEVNHPFI VKLHYAFQTE GKLYLILDFL
160 170 180 190 200
RGGDLFTRLS KEVMFTEEDV KFYLAELALA LDHLHSLGII YRDLKPENIL
210 220 230 240 250
LDEEGHIKLT DFGLSKESID HEKKAYSFCG TVEYMAPEVV NRRGHTQSAD
260 270 280 290 300
WWSFGVLMFE MLTGTLPFQG KDRKETMTMI LKAKLGMPQF LSPEAQSLLR
310 320 330 340 350
MLFKRNPANR LGAGPDGVEE IKRHSFFSTI DWNKLYRREI HPPFKPATGR
360 370 380 390 400
PEDTFYFDPE FTAKTPKDSP GIPPSANAHQ LFRGFSFVAI TSDDESQAMQ
410 420 430 440 450
TVGVHSIVQQ LHRNSIQFTD GYEVKEDIGV GSYSVCKRCI HKATNMEFAV
460 470 480 490 500
KIIDKSKRDP TEEIEILLRY GQHPNIITLK DVYDDGKYVY VVTELMKGGE
510 520 530 540 550
LLDKILRQKF FSEREASAVL FTITKTVEYL HAQGVVHRDL KPSNILYVDE
560 570 580 590 600
SGNPESIRIC DFGFAKQLRA ENGLLMTPCY TANFVAPEVL KRQGYDAACD
610 620 630 640 650
IWSLGVLLYT MLTGYTPFAN GPDDTPEEIL ARIGSGKFSL SGGYWNSVSD
660 670 680 690 700
TAKDLVSKML HVDPHQRLTA ALVLRHPWIV HWDQLPQYQL NRQDAPHLVK
710 720 730 740
GAMAATYSAL NRNQSPVLEP VGRSTLAQRR GIKKITSTAL
Length:740
Mass (Da):83,694
Last modified:March 25, 2003 - v2
Checksum:i0CD54E5918567007
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY083469 mRNA. Translation: AAM00022.1.
AL808146 Genomic DNA. Translation: CAM25836.1.
CCDSiCCDS30502.1.
PIRiC32571.
S30504.
RefSeqiNP_683747.1. NM_148945.2.
UniGeneiMm.328476.
Mm.392829.

Genome annotation databases

EnsembliENSMUST00000033671; ENSMUSP00000033671; ENSMUSG00000031309.
GeneIDi110651.
KEGGimmu:110651.
UCSCiuc009usj.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY083469 mRNA. Translation: AAM00022.1.
AL808146 Genomic DNA. Translation: CAM25836.1.
CCDSiCCDS30502.1.
PIRiC32571.
S30504.
RefSeqiNP_683747.1. NM_148945.2.
UniGeneiMm.328476.
Mm.392829.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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[»]
4M8TX-ray3.00A399-740[»]
4MAOX-ray2.60A399-740[»]
ProteinModelPortaliP18654.
SMRiP18654.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi225783. 10 interactors.
DIPiDIP-31554N.
IntActiP18654. 7 interactors.
MINTiMINT-1486771.
STRINGi10090.ENSMUSP00000033671.

Chemistry databases

ChEMBLiCHEMBL3297641.

PTM databases

iPTMnetiP18654.
PhosphoSitePlusiP18654.
SwissPalmiP18654.

Proteomic databases

EPDiP18654.
MaxQBiP18654.
PaxDbiP18654.
PeptideAtlasiP18654.
PRIDEiP18654.

Protocols and materials databases

DNASUi110651.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000033671; ENSMUSP00000033671; ENSMUSG00000031309.
GeneIDi110651.
KEGGimmu:110651.
UCSCiuc009usj.2. mouse.

Organism-specific databases

CTDi6197.
MGIiMGI:104557. Rps6ka3.

Phylogenomic databases

eggNOGiKOG0598. Eukaryota.
ENOG410XNPH. LUCA.
GeneTreeiENSGT00860000133668.
HOVERGENiHBG108317.
InParanoidiP18654.
KOiK04373.
OMAiYTLNRQD.
OrthoDBiEOG091G05Z7.
PhylomeDBiP18654.
TreeFamiTF313438.

Enzyme and pathway databases

ReactomeiR-MMU-198753. ERK/MAPK targets.
R-MMU-199920. CREB phosphorylation.
R-MMU-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-MMU-442742. CREB phosphorylation through the activation of Ras.
R-MMU-444257. RSK activation.
R-MMU-881907. Gastrin-CREB signalling pathway via PKC and MAPK.

Miscellaneous databases

ChiTaRSiRps6ka3. mouse.
EvolutionaryTraceiP18654.
PROiP18654.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000031309.
CleanExiMM_RPS6KA3.
ExpressionAtlasiP18654. baseline and differential.
GenevisibleiP18654. MM.

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.
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]
ProtoNetiSearch...

Entry informationi

Entry nameiKS6A3_MOUSE
AccessioniPrimary (citable) accession number: P18654
Secondary accession number(s): B1AXN4, Q03140, Q8K3J8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 1, 1990
Last sequence update: March 25, 2003
Last modified: November 30, 2016
This is version 174 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.