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Protein

Ribosomal protein S6 kinase alpha-4

Gene

RPS6KA4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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.3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Cofactori

Mg2+1 Publication

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)DescriptionActionsGraphical viewLength
Binding sitei65ATPPROSITE-ProRule annotation1
Active sitei161Proton acceptorBy similarity1
Binding sitei440ATPPROSITE-ProRule annotation1
Active sitei530Proton acceptorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi39 – 47ATPPROSITE-ProRule annotation9
Nucleotide bindingi417 – 425ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • histone kinase activity (H3-S10 specific) Source: GO_Central
  • magnesium ion binding Source: InterPro
  • mitogen-activated protein kinase p38 binding Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
  • ribosomal protein S6 kinase activity Source: UniProtKB

GO - Biological processi

  • histone H3-S10 phosphorylation Source: UniProtKB
  • histone H3-S28 phosphorylation Source: UniProtKB
  • histone phosphorylation Source: BHF-UCL
  • inflammatory response Source: UniProtKB-KW
  • interleukin-1-mediated signaling pathway Source: BHF-UCL
  • intracellular signal transduction Source: UniProtKB
  • negative regulation of cytokine production Source: UniProtKB
  • positive regulation of CREB transcription factor activity Source: UniProtKB
  • positive regulation of histone acetylation Source: BHF-UCL
  • positive regulation of histone phosphorylation Source: BHF-UCL
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • protein phosphorylation Source: UniProtKB
  • 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, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:HS08656-MONOMER.
ReactomeiR-HSA-437239. Recycling pathway of L1.
SignaLinkiO75676.
SIGNORiO75676.

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
Ribosomal protein kinase B
Short name:
RSKB
Gene namesi
Name:RPS6KA4
Synonyms:MSK2
OrganismiHomo sapiens (Human)Imported
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:10433. RPS6KA4.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: HPA
  • nucleoplasm Source: HPA
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi709F → A: Strongly elevates basal activity. 1 Publication1

Organism-specific databases

DisGeNETi8986.
OpenTargetsiENSG00000162302.
PharmGKBiPA34848.

Chemistry databases

ChEMBLiCHEMBL3125.
GuidetoPHARMACOLOGYi1524.

Polymorphism and mutation databases

BioMutaiRPS6KA4.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862051 – 772Ribosomal protein S6 kinase alpha-4Add BLAST772

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei196Phosphoserine; by autocatalysisBy similarity1
Modified residuei343Phosphoserine; by MAPK1, MAPK3 and MAPK14Curated1
Modified residuei347PhosphoserineCombined sources1
Modified residuei360Phosphoserine; by autocatalysisBy similarity1
Modified residuei365Phosphoserine; by autocatalysisBy similarity1
Modified residuei542PhosphothreonineCombined sources1
Modified residuei568Phosphothreonine; by MAPK1, MAPK3 and MAPK14By similarity1
Modified residuei634PhosphoserineCombined sources1
Modified residuei678PhosphoserineCombined sources1
Modified residuei687PhosphothreonineCombined sources1
Modified residuei737Phosphoserine; by autocatalysisCurated1
Modified residuei745PhosphoserineCombined sources1

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

EPDiO75676.
MaxQBiO75676.
PaxDbiO75676.
PeptideAtlasiO75676.
PRIDEiO75676.

PTM databases

iPTMnetiO75676.
PhosphoSitePlusiO75676.

Expressioni

Gene expression databases

BgeeiENSG00000162302.
CleanExiHS_RPS6KA4.
ExpressionAtlasiO75676. baseline and differential.
GenevisibleiO75676. HS.

Organism-specific databases

HPAiCAB008649.
HPA023225.

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.

Binary interactionsi

WithEntry#Exp.IntActNotes
MAPK14Q165394EBI-73933,EBI-73946

GO - Molecular functioni

  • mitogen-activated protein kinase p38 binding Source: UniProtKB

Protein-protein interaction databases

BioGridi114468. 15 interactors.
IntActiO75676. 5 interactors.
MINTiMINT-7944429.
STRINGi9606.ENSP00000333896.

Chemistry databases

BindingDBiO75676.

Structurei

3D structure databases

ProteinModelPortaliO75676.
SMRiO75676.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini33 – 301Protein kinase 1PROSITE-ProRule annotationAdd BLAST269
Domaini302 – 371AGC-kinase C-terminalAdd BLAST70
Domaini411 – 674Protein kinase 2PROSITE-ProRule annotationAdd BLAST264

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni725 – 772Required for nuclear targeting and association with MAPK14Add BLAST48

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.
HOGENOMiHOG000233033.
HOVERGENiHBG108317.
InParanoidiO75676.
KOiK16510.
OMAiYHTYLVM.
OrthoDBiEOG091G01KO.
PhylomeDBiO75676.
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]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O75676-1) [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
MGDEDDDESC AVELRITEAN LTGHEEKVSV ENFELLKVLG TGAYGKVFLV
60 70 80 90 100
RKAGGHDAGK 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 SKTGHGKAVD WWSLGILLFE LLTGASPFTL EGERNTQAEV
260 270 280 290 300
SRRILKCSPP FPPRIGPVAQ DLLQRLLCKD PKKRLGAGPQ GAQEVRNHPF
310 320 330 340 350
FQGLDWVALA ARKIPAPFRP QIRSELDVGN FAEEFTRLEP VYSPPGSPPP
360 370 380 390 400
GDPRIFQGYS FVAPSILFDH NNAVMTDGLE APGAGDRPGR AAVARSAMMQ
410 420 430 440 450
DSPFFQQYEL DLREPALGQG SFSVCRRCRQ RQSGQEFAVK ILSRRLEANT
460 470 480 490 500
QREVAALRLC QSHPNVVNLH EVHHDQLHTY LVLELLRGGE LLEHIRKKRH
510 520 530 540 550
FSESEASQIL RSLVSAVSFM HEEAGVVHRD LKPENILYAD DTPGAPVKII
560 570 580 590 600
DFGFARLRPQ SPGVPMQTPC FTLQYAAPEL LAQQGYDESC DLWSLGVILY
610 620 630 640 650
MMLSGQVPFQ GASGQGGQSQ AAEIMCKIRE GRFSLDGEAW QGVSEEAKEL
660 670 680 690 700
VRGLLTVDPA KRLKLEGLRG SSWLQDGSAR SSPPLRTPDV LESSGPAVRS
710 720 730 740 750
GLNATFMAFN RGKREGFFLK SVENAPLAKR RKQKLRSATA SRRGSPAPAN
760 770
PGRAPVASKG APRRANGPLP PS
Length:772
Mass (Da):85,606
Last modified:November 1, 1998 - v1
Checksum:i3606209693D0B5F3
GO
Isoform 2 (identifier: O75676-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     401-406: Missing.

Show »
Length:766
Mass (Da):84,884
Checksum:iDE27817E248DA71E
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti477L → P in BAD97281 (Ref. 3) Curated1
Isoform 2 (identifier: O75676-2)
Sequence conflicti400 – 401QQ → Q in BAD97281 (Ref. 3) Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040632236S → L in a breast infiltrating ductal carcinoma sample; somatic mutation. 1 PublicationCorresponds to variant rs746466314dbSNPEnsembl.1
Natural variantiVAR_040633758S → A.2 PublicationsCorresponds to variant rs17857342dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_017733401 – 406Missing in isoform 2. 2 Publications6

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ010119 mRNA. Translation: CAA09009.1.
AK223561 mRNA. Translation: BAD97281.1.
AK292163 mRNA. Translation: BAF84852.1.
CH471076 Genomic DNA. Translation: EAW74260.1.
AF074715 mRNA. Translation: AAC67395.1.
CCDSiCCDS8073.1. [O75676-1]
RefSeqiNP_001006945.1. NM_001006944.1. [O75676-2]
NP_001287731.1. NM_001300802.1.
NP_001305290.1. NM_001318361.1.
NP_003933.1. NM_003942.2. [O75676-1]
UniGeneiHs.105584.

Genome annotation databases

EnsembliENST00000334205; ENSP00000333896; ENSG00000162302. [O75676-1]
GeneIDi8986.
KEGGihsa:8986.
UCSCiuc001oae.4. human. [O75676-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ010119 mRNA. Translation: CAA09009.1.
AK223561 mRNA. Translation: BAD97281.1.
AK292163 mRNA. Translation: BAF84852.1.
CH471076 Genomic DNA. Translation: EAW74260.1.
AF074715 mRNA. Translation: AAC67395.1.
CCDSiCCDS8073.1. [O75676-1]
RefSeqiNP_001006945.1. NM_001006944.1. [O75676-2]
NP_001287731.1. NM_001300802.1.
NP_001305290.1. NM_001318361.1.
NP_003933.1. NM_003942.2. [O75676-1]
UniGeneiHs.105584.

3D structure databases

ProteinModelPortaliO75676.
SMRiO75676.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi114468. 15 interactors.
IntActiO75676. 5 interactors.
MINTiMINT-7944429.
STRINGi9606.ENSP00000333896.

Chemistry databases

BindingDBiO75676.
ChEMBLiCHEMBL3125.
GuidetoPHARMACOLOGYi1524.

PTM databases

iPTMnetiO75676.
PhosphoSitePlusiO75676.

Polymorphism and mutation databases

BioMutaiRPS6KA4.

Proteomic databases

EPDiO75676.
MaxQBiO75676.
PaxDbiO75676.
PeptideAtlasiO75676.
PRIDEiO75676.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000334205; ENSP00000333896; ENSG00000162302. [O75676-1]
GeneIDi8986.
KEGGihsa:8986.
UCSCiuc001oae.4. human. [O75676-1]

Organism-specific databases

CTDi8986.
DisGeNETi8986.
GeneCardsiRPS6KA4.
HGNCiHGNC:10433. RPS6KA4.
HPAiCAB008649.
HPA023225.
MIMi603606. gene.
neXtProtiNX_O75676.
OpenTargetsiENSG00000162302.
PharmGKBiPA34848.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0598. Eukaryota.
ENOG410XNPH. LUCA.
GeneTreeiENSGT00860000133668.
HOGENOMiHOG000233033.
HOVERGENiHBG108317.
InParanoidiO75676.
KOiK16510.
OMAiYHTYLVM.
OrthoDBiEOG091G01KO.
PhylomeDBiO75676.
TreeFamiTF313438.

Enzyme and pathway databases

BioCyciZFISH:HS08656-MONOMER.
ReactomeiR-HSA-437239. Recycling pathway of L1.
SignaLinkiO75676.
SIGNORiO75676.

Miscellaneous databases

ChiTaRSiRPS6KA4. human.
GeneWikiiRPS6KA4.
GenomeRNAii8986.
PROiO75676.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000162302.
CleanExiHS_RPS6KA4.
ExpressionAtlasiO75676. baseline and differential.
GenevisibleiO75676. HS.

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 nameiKS6A4_HUMAN
AccessioniPrimary (citable) accession number: O75676
Secondary accession number(s): A8K7Z8, O75585, Q53ES8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 24, 2003
Last sequence update: November 1, 1998
Last modified: November 30, 2016
This is version 166 of the entry and version 1 of the sequence. [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

Miscellaneous

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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  6. 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.