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UniProtKB - O75676 (KS6A4_HUMAN)

Protein

Ribosomal protein S6 kinase alpha-4

Gene

RPS6KA4

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

Miscellaneous

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

Catalytic activityi

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

Cofactori

Mg2+1 Publication

Activity 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
  • magnesium ion binding Source: InterPro
  • protein serine/threonine kinase activity Source: UniProtKB
  • ribosomal protein S6 kinase activity Source: UniProtKB
View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processInflammatory response, Stress response
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

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 lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

EuPathDBiHostDB:ENSG00000162302.12
HGNCiHGNC:10433 RPS6KA4
MIMi603606 gene
neXtProtiNX_O75676

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
DrugBankiDB03247 Riboflavin Monophosphate
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
ProteomicsDBi50149
50150 [O75676-2]

PTM databases

iPTMnetiO75676
PhosphoSitePlusiO75676

Expressioni

Gene expression databases

BgeeiENSG00000162302 Expressed in 178 organ(s), highest expression level in cerebellar hemisphere
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

Protein-protein interaction databases

BioGridi114468, 26 interactors
ELMiO75676
IntActiO75676, 6 interactors
MINTiO75676
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

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

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00920000148962
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiO75676
KOiK16510
OMAiEEFTGMD
OrthoDBiEOG091G01KO
PhylomeDBiO75676
TreeFamiTF313438

Family and domain databases

CDDicd05614 STKc_MSK2_N, 1 hit
InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR011009 Kinase-like_dom_sf
IPR037714 MSK2_N_dom
IPR017892 Pkinase_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR016239 Ribosomal_S6_kinase_II
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
PF00433 Pkinase_C, 1 hit
PIRSFiPIRSF000606 Ribsml_S6_kin_2, 1 hit
SMARTiView protein in SMART
SM00133 S_TK_X, 1 hit
SM00220 S_TKc, 2 hits
SUPFAMiSSF56112 SSF56112, 2 hits
PROSITEiView protein in PROSITE
PS51285 AGC_KINASE_CTER, 1 hit
PS00107 PROTEIN_KINASE_ATP, 2 hits
PS50011 PROTEIN_KINASE_DOM, 2 hits
PS00108 PROTEIN_KINASE_ST, 2 hits

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 3 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
E9PJN1E9PJN1_HUMAN
Ribosomal protein S6 kinase
RPS6KA4
765Annotation score:
A0A0A6YYC0A0A0A6YYC0_HUMAN
Ribosomal protein S6 kinase alpha-4
RPS6KA4
704Annotation score:
E9PKU3E9PKU3_HUMAN
Ribosomal protein S6 kinase alpha-4
RPS6KA4
48Annotation score:

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 dbSNP:rs746466314Ensembl.1
Natural variantiVAR_040633758S → A2 PublicationsCorresponds to variant dbSNP:rs17857342Ensembl.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

Similar proteinsi

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, 26 interactors
ELMiO75676
IntActiO75676, 6 interactors
MINTiO75676
STRINGi9606.ENSP00000333896

Chemistry databases

BindingDBiO75676
ChEMBLiCHEMBL3125
DrugBankiDB03247 Riboflavin Monophosphate
GuidetoPHARMACOLOGYi1524

PTM databases

iPTMnetiO75676
PhosphoSitePlusiO75676

Polymorphism and mutation databases

BioMutaiRPS6KA4

Proteomic databases

EPDiO75676
MaxQBiO75676
PaxDbiO75676
PeptideAtlasiO75676
PRIDEiO75676
ProteomicsDBi50149
50150 [O75676-2]

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
EuPathDBiHostDB:ENSG00000162302.12
GeneCardsiRPS6KA4
HGNCiHGNC:10433 RPS6KA4
HPAiCAB008649
HPA023225
MIMi603606 gene
neXtProtiNX_O75676
OpenTargetsiENSG00000162302
PharmGKBiPA34848
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00920000148962
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiO75676
KOiK16510
OMAiEEFTGMD
OrthoDBiEOG091G01KO
PhylomeDBiO75676
TreeFamiTF313438

Enzyme and pathway databases

ReactomeiR-HSA-437239 Recycling pathway of L1
SignaLinkiO75676
SIGNORiO75676

Miscellaneous databases

ChiTaRSiRPS6KA4 human
GeneWikiiRPS6KA4
GenomeRNAii8986
PROiPR:O75676
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000162302 Expressed in 178 organ(s), highest expression level in cerebellar hemisphere
CleanExiHS_RPS6KA4
ExpressionAtlasiO75676 baseline and differential
GenevisibleiO75676 HS

Family and domain databases

CDDicd05614 STKc_MSK2_N, 1 hit
InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR011009 Kinase-like_dom_sf
IPR037714 MSK2_N_dom
IPR017892 Pkinase_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR016239 Ribosomal_S6_kinase_II
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 2 hits
PF00433 Pkinase_C, 1 hit
PIRSFiPIRSF000606 Ribsml_S6_kin_2, 1 hit
SMARTiView protein in SMART
SM00133 S_TK_X, 1 hit
SM00220 S_TKc, 2 hits
SUPFAMiSSF56112 SSF56112, 2 hits
PROSITEiView protein in PROSITE
PS51285 AGC_KINASE_CTER, 1 hit
PS00107 PROTEIN_KINASE_ATP, 2 hits
PS50011 PROTEIN_KINASE_DOM, 2 hits
PS00108 PROTEIN_KINASE_ST, 2 hits
ProtoNetiSearch...

Entry informationi

Entry nameiKS6A4_HUMAN
AccessioniPrimary (citable) accession number: O75676
Secondary accession number(s): A8K7Z8, O75585, Q53ES8
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 24, 2003
Last sequence update: November 1, 1998
Last modified: October 10, 2018
This is version 178 of the entry and version 1 of the sequence. See 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

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

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