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UniProtKB - O75582 (KS6A5_HUMAN)

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Protein

Ribosomal protein S6 kinase alpha-5

Gene

RPS6KA5

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 factors RELA, STAT3 and ETV1/ER81, 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 and upon glucocorticoid, associates in the cytoplasm with the glucocorticoid receptor NR3C1 and contributes to RELA inhibition and repression of inflammatory gene expression. In skeletal myoblasts is required for phosphorylation of RELA at 'Ser-276' during oxidative stress. In erythropoietin-stimulated cells, is necessary for the 'Ser-727' phosphorylation of STAT3 and regulation of its transcriptional potential. Phosphorylates ETV1/ER81 at 'Ser-191' and 'Ser-216', and thereby regulates its ability to stimulate transcription, which may be important during development and breast tumor formation. Directly represses transcription via phosphorylation of 'Ser-1' of histone H2A. 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. Plays a role in neuronal cell death by mediating the downstream effects of excitotoxic injury.9 Publications

Miscellaneous

Enzyme activity requires the presence of both kinase domains.1 Publication

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.3 Publications

Cofactori

Mg2+3 Publications

Enzyme regulationi

Activated by phosphorylation at Ser-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha, and by further autophosphorylation of Ser-212, Ser-376 and Ser-381 by the activated C-terminal kinase domain. The active N-terminal kinase domain finally phosphorylates downstream substrates, as well as Ser-750, Ser-752 and Ser-758 in its own C-terminal region.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei81ATPPROSITE-ProRule annotation1
Active sitei177Proton acceptorBy similarity1
Binding sitei455ATPPROSITE-ProRule annotation1
Active sitei544Proton acceptorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi55 – 63ATPPROSITE-ProRule annotation9
Nucleotide bindingi432 – 440ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • magnesium ion binding Source: InterPro
  • protein kinase activity Source: UniProtKB
  • protein serine/threonine kinase activity Source: UniProtKB
Complete GO annotation...

GO - Biological processi

  • axon guidance Source: Reactome
  • epidermal growth factor receptor signaling pathway Source: UniProtKB
  • histone H2A-S1 phosphorylation Source: UniProtKB
  • histone H3-S10 phosphorylation Source: UniProtKB
  • histone H3-S28 phosphorylation Source: UniProtKB
  • histone phosphorylation Source: UniProtKB
  • 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
  • negative regulation of transcription, DNA-templated 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
  • stimulatory C-type lectin receptor signaling pathway Source: Reactome
Complete GO annotation...

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-198753. ERK/MAPK targets.
R-HSA-199920. CREB phosphorylation.
R-HSA-375165. NCAM signaling for neurite out-growth.
R-HSA-437239. Recycling pathway of L1.
R-HSA-5621575. CD209 (DC-SIGN) signaling.
SABIO-RKiO75582.
SignaLinkiO75582.
SIGNORiO75582.

Names & Taxonomyi

Protein namesi
Recommended name:
Ribosomal protein S6 kinase alpha-5 (EC:2.7.11.1)
Short name:
S6K-alpha-5
Alternative name(s):
90 kDa ribosomal protein S6 kinase 5
Nuclear mitogen- and stress-activated protein kinase 1
RSK-like protein kinase
Short name:
RSKL
Gene namesi
Name:RPS6KA5
Synonyms:MSK1
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 14

Organism-specific databases

EuPathDBiHostDB:ENSG00000100784.9.
HGNCiHGNC:10434. RPS6KA5.

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

Cytoplasm, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi195D → A: Loss of kinase activity. 1 Publication1
Mutagenesisi212S → A: Inactivates the N-terminal kinase domain. 1 Publication1
Mutagenesisi360S → A: Decreases kinase activity by 60% in response to PMA and UV-C. 1 Publication1
Mutagenesisi376S → A: Loss of kinase activity, and decreases the phosphorylation of S-360 and T-581. 1 Publication1
Mutagenesisi565D → A: Loss of kinase activity. 1 Publication1
Mutagenesisi581T → A: Loss of kinase activity, and blocks phosphorylation of S-212; S-376 and S-381 in response to PMA and UV-C. 1 Publication1
Mutagenesisi700T → A or D: Strongly reduces phosphorylation of T-581 in response to PMA and UV-C. 1 Publication1

Organism-specific databases

DisGeNETi9252.
OpenTargetsiENSG00000100784.
PharmGKBiPA34849.

Chemistry databases

ChEMBLiCHEMBL4237.
GuidetoPHARMACOLOGYi1523.

Polymorphism and mutation databases

BioMutaiRPS6KA5.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862071 – 802Ribosomal protein S6 kinase alpha-5Add BLAST802

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei212Phosphoserine; by autocatalysis1 Publication1
Modified residuei360Phosphoserine; by MAPK1, MAPK3 and MAPK141 Publication1
Modified residuei376Phosphoserine; by autocatalysisCombined sources1 Publication1
Modified residuei381Phosphoserine; by autocatalysisCombined sources1 Publication1
Modified residuei581Phosphothreonine; by MAPK1, MAPK3 and MAPK141 Publication1
Modified residuei647Phosphoserine1 Publication1
Modified residuei657Phosphoserine1 Publication1
Modified residuei691PhosphoserineBy similarity1
Modified residuei695Phosphoserine1 Publication1
Modified residuei700Phosphothreonine; by MAPK1, MAPK3 and MAPK141 Publication1
Modified residuei750Phosphoserine; by autocatalysis1 Publication1
Modified residuei752Phosphoserine; by autocatalysis1 Publication1
Modified residuei758Phosphoserine; by autocatalysis1 Publication1
Modified residuei798PhosphoserineBy similarity1

Post-translational modificationi

Ser-376 and Thr-581 phosphorylation is required for kinase activity. Ser-376 and Ser-212 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-360, Thr-581 and Thr-700 by MAPK1/ERK2, MAPK3/ERK1 and MAPK14/p38-alpha. Autophosphorylated at Ser-750, Ser-752 and Ser-758 by the N-terminal kinase domain.2 Publications
Ubiquitinated.1 Publication

Keywords - PTMi

Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO75582.
MaxQBiO75582.
PaxDbiO75582.
PeptideAtlasiO75582.
PRIDEiO75582.

PTM databases

iPTMnetiO75582.
PhosphoSitePlusiO75582.

Expressioni

Tissue specificityi

Widely expressed with high levels in heart, brain and placenta. Less abundant in lung, kidney and liver.2 Publications

Gene expression databases

BgeeiENSG00000100784.
CleanExiHS_RPS6KA5.
ExpressionAtlasiO75582. baseline and differential.
GenevisibleiO75582. HS.

Organism-specific databases

HPAiCAB025458.
HPA001274.
HPA001780.

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 RPS6KA5 associates with and phosphorylates the NF-kappa-B p65 subunit RELA. Interacts with CREBBP and EP300.2 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi114676. 55 interactors.
DIPiDIP-30894N.
ELMiO75582.
IntActiO75582. 36 interactors.
MINTiMINT-261060.
STRINGi9606.ENSP00000261991.

Chemistry databases

BindingDBiO75582.

Structurei

Secondary structure

1802
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi26 – 31Combined sources6
Helixi46 – 48Combined sources3
Beta strandi49 – 57Combined sources9
Turni58 – 60Combined sources3
Beta strandi61 – 68Combined sources8
Turni72 – 75Combined sources4
Beta strandi77 – 94Combined sources18
Helixi95 – 97Combined sources3
Helixi101 – 109Combined sources9
Beta strandi117 – 123Combined sources7
Beta strandi126 – 131Combined sources6
Helixi139 – 146Combined sources8
Helixi151 – 170Combined sources20
Helixi180 – 182Combined sources3
Beta strandi183 – 185Combined sources3
Beta strandi191 – 194Combined sources4
Beta strandi196 – 201Combined sources6
Helixi204 – 210Combined sources7
Helixi212 – 214Combined sources3
Helixi222 – 225Combined sources4
Helixi235 – 250Combined sources16
Helixi264 – 273Combined sources10
Helixi284 – 293Combined sources10
Helixi298 – 300Combined sources3
Turni306 – 308Combined sources3
Helixi309 – 313Combined sources5
Helixi316 – 318Combined sources3
Helixi323 – 327Combined sources5
Helixi418 – 422Combined sources5
Beta strandi423 – 425Combined sources3
Beta strandi432 – 435Combined sources4
Beta strandi438 – 445Combined sources8
Turni446 – 448Combined sources3
Beta strandi451 – 458Combined sources8
Helixi459 – 461Combined sources3
Helixi462 – 474Combined sources13
Turni475 – 477Combined sources3
Beta strandi484 – 489Combined sources6
Beta strandi491 – 498Combined sources8
Helixi506 – 512Combined sources7
Helixi518 – 537Combined sources20
Helixi547 – 549Combined sources3
Beta strandi550 – 553Combined sources4
Beta strandi560 – 563Combined sources4
Helixi602 – 617Combined sources16
Helixi634 – 641Combined sources8
Turni642 – 644Combined sources3
Helixi651 – 654Combined sources4
Helixi658 – 668Combined sources11
Turni672 – 674Combined sources3
Turni678 – 680Combined sources3
Helixi685 – 687Combined sources3
Helixi700 – 728Combined sources29

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1VZOX-ray1.80A2-348[»]
3KN5X-ray2.40A/B414-738[»]
3KN6X-ray2.00A/B414-738[»]
ProteinModelPortaliO75582.
SMRiO75582.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiO75582.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini49 – 318Protein kinase 1PROSITE-ProRule annotationAdd BLAST270
Domaini319 – 387AGC-kinase C-terminalAdd BLAST69
Domaini426 – 687Protein kinase 2PROSITE-ProRule annotationAdd BLAST262

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.
GeneTreeiENSGT00890000139324.
HOGENOMiHOG000233033.
HOVERGENiHBG108317.
InParanoidiO75582.
KOiK04445.
OMAiAPSILFK.
PhylomeDBiO75582.
TreeFamiTF313438.

Family and domain databases

InterProiView protein in InterPro
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.
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 (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O75582-1) [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
MEEEGGSSGG AAGTSADGGD GGEQLLTVKH ELRTANLTGH AEKVGIENFE 
        60         70         80         90        100
LLKVLGTGAY GKVFLVRKIS GHDTGKLYAM KVLKKATIVQ KAKTTEHTRT 
       110        120        130        140        150
ERQVLEHIRQ SPFLVTLHYA FQTETKLHLI LDYINGGELF THLSQRERFT 
       160        170        180        190        200
EHEVQIYVGE IVLALEHLHK LGIIYRDIKL ENILLDSNGH VVLTDFGLSK 
       210        220        230        240        250
EFVADETERA YSFCGTIEYM APDIVRGGDS GHDKAVDWWS LGVLMYELLT 
       260        270        280        290        300
GASPFTVDGE KNSQAEISRR ILKSEPPYPQ EMSALAKDLI QRLLMKDPKK 
       310        320        330        340        350
RLGCGPRDAD EIKEHLFFQK INWDDLAAKK VPAPFKPVIR DELDVSNFAE 
       360        370        380        390        400
EFTEMDPTYS PAALPQSSEK LFQGYSFVAP SILFKRNAAV IDPLQFHMGV 
       410        420        430        440        450
ERPGVTNVAR SAMMKDSPFY QHYDLDLKDK PLGEGSFSIC RKCVHKKSNQ 
       460        470        480        490        500
AFAVKIISKR MEANTQKEIT ALKLCEGHPN IVKLHEVFHD QLHTFLVMEL 
       510        520        530        540        550
LNGGELFERI KKKKHFSETE ASYIMRKLVS AVSHMHDVGV VHRDLKPENL 
       560        570        580        590        600
LFTDENDNLE IKIIDFGFAR LKPPDNQPLK TPCFTLHYAA PELLNQNGYD 
       610        620        630        640        650
ESCDLWSLGV ILYTMLSGQV PFQSHDRSLT CTSAVEIMKK IKKGDFSFEG 
       660        670        680        690        700
EAWKNVSQEA KDLIQGLLTV DPNKRLKMSG LRYNEWLQDG SQLSSNPLMT 
       710        720        730        740        750
PDILGSSGAA VHTCVKATFH AFNKYKREGF CLQNVDKAPL AKRRKMKKTS 
       760        770        780        790        800
TSTETRSSSS ESSHSSSSHS HGKTTPTKTL QPSNPADSNN PETLFQFSDS 

VA
Length:802
Mass (Da):89,865
Last modified:November 1, 1998 - v1
Checksum:i76C27D0F6639BFA4
GO
Isoform 2 (identifier: O75582-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     549-549: N → V
     550-802: Missing.

Show »
Length:549
Mass (Da):61,769
Checksum:i3CED0A0C50E96C78
GO
Isoform 3 (identifier: O75582-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-79: Missing.

Note: No experimental confirmation available.
Show »
Length:723
Mass (Da):81,780
Checksum:i19C49A91CAAA0CBF
GO

Sequence cautioni

The sequence AAC69577 differs from that shown. Reason: Frameshift at several positions.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti452 – 453FA → LQ in AAC69577 (PubMed:10702687).Curated2
Sequence conflicti532V → L in AAC69577 (PubMed:10702687).Curated1
Sequence conflicti538V → L in AAC69577 (PubMed:10702687).Curated1
Sequence conflicti757 – 758SS → RG in AAC69577 (PubMed:10702687).Curated2

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_051634190H → R. Corresponds to variant dbSNP:rs34699345Ensembl.1
Natural variantiVAR_040634554D → N1 PublicationCorresponds to variant dbSNP:rs55911249Ensembl.1
Natural variantiVAR_040635574P → L1 PublicationCorresponds to variant dbSNP:rs34604933Ensembl.1
Natural variantiVAR_040636599Y → C1 PublicationCorresponds to variant dbSNP:rs55968863Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0574101 – 79Missing in isoform 3. 1 PublicationAdd BLAST79
Alternative sequenceiVSP_041837549N → V in isoform 2. 1 Publication1
Alternative sequenceiVSP_041838550 – 802Missing in isoform 2. 1 PublicationAdd BLAST253

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF074393 mRNA. Translation: AAC31171.1.
AF080000 mRNA. Translation: AAD23915.1.
AF090421 mRNA. Translation: AAC69577.1. Frameshift.
AK295266 mRNA. Translation: BAH12021.1.
AL121784 Genomic DNA. No translation available.
AL133454 Genomic DNA. No translation available.
AL159191 Genomic DNA. No translation available.
BC017187 mRNA. Translation: AAH17187.1.
CCDSiCCDS45149.1. [O75582-2]
CCDS81839.1. [O75582-3]
CCDS9893.1. [O75582-1]
PIRiT13149.
RefSeqiNP_001309164.1. NM_001322235.1. [O75582-3]
NP_001309166.1. NM_001322237.1. [O75582-3]
NP_004746.2. NM_004755.3. [O75582-1]
NP_872198.1. NM_182398.2. [O75582-2]
UniGeneiHs.510225.

Genome annotation databases

EnsembliENST00000418736; ENSP00000402787; ENSG00000100784. [O75582-2]
ENST00000536315; ENSP00000442803; ENSG00000100784. [O75582-3]
ENST00000614987; ENSP00000479667; ENSG00000100784. [O75582-1]
GeneIDi9252.
KEGGihsa:9252.
UCSCiuc001xys.4. human. [O75582-1]
uc010twi.3. human.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiKS6A5_HUMAN
AccessioniPrimary (citable) accession number: O75582
Secondary accession number(s): B7Z2Y5, O95316, Q96AF7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 24, 2003
Last sequence update: November 1, 1998
Last modified: September 27, 2017
This is version 179 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families