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UniProtKB - Q15418 (KS6A1_HUMAN)

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Protein

Ribosomal protein S6 kinase alpha-1

Gene

RPS6KA1

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 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, 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 pre-initiation 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). Mediates induction of hepatocyte prolifration by TGFA through phosphorylation of CEBPB (By similarity). 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. Phosphorylates EPHA2 at 'Ser-897', the RPS6KA-EPHA2 signaling pathway controls cell migration (PubMed:26158630).By similarity12 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Mg2+

Enzyme regulationi

Upon extracellular signal or mitogen stimulation, phosphorylated at Thr-573 in the C-terminal kinase domain (CTKD) by MAPK1/ERK2 and MAPK3/ERK1. The activated CTKD then autophosphorylates Ser-380, allowing binding of PDPK1, which in turn phosphorylates Ser-221 in the N-terminal kinase domain (NTDK) leading to the full activation of the protein and subsequent phosphorylation of the substrates by the NTKD.2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei94ATPPROSITE-ProRule annotation1
Active sitei187Proton acceptorBy similarity1
Binding sitei447ATPPROSITE-ProRule annotation1
Active sitei535Proton acceptorBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi68 – 76ATPPROSITE-ProRule annotation9
Nucleotide bindingi424 – 432ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cysteine-type endopeptidase inhibitor activity involved in apoptotic process Source: UniProtKB
  • kinase activity Source: Reactome
  • magnesium ion binding Source: InterPro
  • protein serine/threonine/tyrosine kinase activity Source: MGI
  • protein serine/threonine kinase activity Source: UniProtKB
Complete GO annotation...

GO - Biological processi

  • cell cycle Source: UniProtKB-KW
  • hepatocyte proliferation Source: UniProtKB
  • intracellular signal transduction Source: GO_Central
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • positive regulation of cell differentiation Source: UniProtKB
  • positive regulation of cell growth Source: UniProtKB
  • positive regulation of hepatic stellate cell activation Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: BHF-UCL
  • regulation of DNA-templated transcription in response to stress Source: UniProtKB
  • regulation of translation in response to stress Source: UniProtKB
  • signal transduction Source: ProtInc
Complete GO annotation...

Keywordsi

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

Enzyme and pathway databases

BRENDAi2.7.11.1. 2681.
ReactomeiR-HSA-198753. ERK/MAPK targets.
R-HSA-199920. CREB phosphorylation.
R-HSA-2559582. Senescence-Associated Secretory Phenotype (SASP).
R-HSA-437239. Recycling pathway of L1.
R-HSA-442742. CREB phosphorylation through the activation of Ras.
R-HSA-444257. RSK activation.
R-HSA-881907. Gastrin-CREB signalling pathway via PKC and MAPK.
SABIO-RKiQ15418.
SignaLinkiQ15418.
SIGNORiQ15418.

Names & Taxonomyi

Protein namesi
Recommended name:
Ribosomal protein S6 kinase alpha-1 (EC:2.7.11.1)
Short name:
S6K-alpha-1
Alternative name(s):
90 kDa ribosomal protein S6 kinase 1
Short name:
p90-RSK 1
Short name:
p90RSK1
Short name:
p90S6K
MAP kinase-activated protein kinase 1a
Short name:
MAPK-activated protein kinase 1a
Short name:
MAPKAP kinase 1a
Short name:
MAPKAPK-1a
Ribosomal S6 kinase 1
Short name:
RSK-1
Gene namesi
Name:RPS6KA1
Synonyms:MAPKAPK1A, RSK1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:10430. RPS6KA1.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

Pathology & Biotechi

Organism-specific databases

DisGeNETi6195.
OpenTargetsiENSG00000117676.
PharmGKBiPA34845.

Chemistry databases

ChEMBLiCHEMBL2553.
DrugBankiDB04751. Purvalanol A.
GuidetoPHARMACOLOGYi1527.

Polymorphism and mutation databases

BioMutaiRPS6KA1.
DMDMi20178306.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000861981 – 735Ribosomal protein S6 kinase alpha-1Add BLAST735

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei54PhosphoserineCombined sources1
Modified residuei221Phosphoserine; by PDPK11 Publication1
Modified residuei307PhosphoserineCombined sources1
Modified residuei359PhosphothreonineCombined sources1 Publication1
Modified residuei363PhosphoserineCombined sources1 Publication1
Modified residuei369PhosphoserineCombined sources1
Modified residuei380Phosphoserine; by autocatalysisCombined sources1 Publication1
Modified residuei573Phosphothreonine1 Publication1
Modified residuei732Phosphoserine1 Publication1

Post-translational modificationi

Activated by phosphorylation at Ser-221 by PDPK1. Autophosphorylated on Ser-380, as part of the activation process. May be phosphorylated at Thr-359 and Ser-363 by MAPK1/ERK2 and MAPK3/ERK1.1 Publication
N-terminal myristoylation results in an activated kinase in the absence of added growth factors.

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ15418.
MaxQBiQ15418.
PaxDbiQ15418.
PeptideAtlasiQ15418.
PRIDEiQ15418.

2D gel databases

UCD-2DPAGEiQ15418.

PTM databases

iPTMnetiQ15418.
PhosphoSitePlusiQ15418.

Expressioni

Gene expression databases

BgeeiENSG00000117676.
CleanExiHS_RPS6KA1.
ExpressionAtlasiQ15418. baseline and differential.
GenevisibleiQ15418. HS.

Organism-specific databases

HPAiCAB003852.
HPA007981.

Interactioni

Subunit structurei

Forms a complex with either MAPK1/ERK2 or MAPK3/ERK1 in quiescent cells. Transiently dissociates following mitogenic stimulation. Interacts with ETV1/ER81 and FGFR1.5 Publications

Binary interactionsi

Show more details

Protein-protein interaction databases

BioGridi112109. 70 interactors.
DIPiDIP-29987N.
IntActiQ15418. 30 interactors.
MINTiMINT-207205.
STRINGi9606.ENSP00000435412.

Chemistry databases

BindingDBiQ15418.

Structurei

Secondary structure

1735
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi59 – 61Combined sources3
Beta strandi62 – 71Combined sources10
Beta strandi74 – 81Combined sources8
Beta strandi83 – 86Combined sources4
Beta strandi90 – 96Combined sources7
Beta strandi127 – 133Combined sources7
Beta strandi136 – 141Combined sources6
Helixi149 – 156Combined sources8
Helixi161 – 180Combined sources20
Helixi190 – 192Combined sources3
Beta strandi193 – 195Combined sources3
Beta strandi197 – 199Combined sources3
Beta strandi201 – 203Combined sources3
Helixi226 – 228Combined sources3
Helixi231 – 234Combined sources4
Helixi241 – 257Combined sources17
Helixi267 – 276Combined sources10
Helixi287 – 296Combined sources10
Turni301 – 303Combined sources3
Beta strandi307 – 310Combined sources4
Helixi312 – 316Combined sources5
Helixi319 – 321Combined sources3
Helixi326 – 330Combined sources5
Beta strandi418 – 427Combined sources10
Beta strandi430 – 437Combined sources8
Turni438 – 441Combined sources4
Beta strandi442 – 450Combined sources9
Turni451 – 453Combined sources3
Helixi457 – 466Combined sources10
Beta strandi475 – 480Combined sources6
Beta strandi482 – 490Combined sources9
Helixi497 – 501Combined sources5
Beta strandi503 – 505Combined sources3
Helixi509 – 528Combined sources20
Helixi538 – 540Combined sources3
Beta strandi541 – 547Combined sources7
Helixi550 – 552Combined sources3
Beta strandi553 – 555Combined sources3
Turni574 – 576Combined sources3
Helixi583 – 609Combined sources27
Helixi622 – 631Combined sources10
Helixi639 – 642Combined sources4
Helixi646 – 655Combined sources10
Helixi660 – 662Combined sources3
Helixi666 – 671Combined sources6
Helixi673 – 676Combined sources4
Helixi678 – 680Combined sources3
Helixi691 – 706Combined sources16
Helixi717 – 719Combined sources3
Helixi721 – 726Combined sources6

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2WNTX-ray2.40A/B413-719[»]
2Z7QX-ray2.00A33-353[»]
2Z7RX-ray2.00A33-353[»]
2Z7SX-ray2.10A33-353[»]
3RNYX-ray2.70A/B411-735[»]
3TEIX-ray2.40B712-735[»]
4H3PX-ray2.30B/E712-735[»]
4NIFX-ray2.15A/D411-735[»]
5CSFX-ray2.40C683-735[»]
5CSIX-ray2.13C689-735[»]
5CSJX-ray2.70C696-735[»]
5CSNX-ray2.95C683-720[»]
ProteinModelPortaliQ15418.
SMRiQ15418.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15418.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini62 – 321Protein kinase 1PROSITE-ProRule annotationAdd BLAST260
Domaini322 – 391AGC-kinase C-terminalAdd BLAST70
Domaini418 – 675Protein kinase 2PROSITE-ProRule annotationAdd BLAST258

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.
GeneTreeiENSGT00880000137853.
HOVERGENiHBG108317.
InParanoidiQ15418.
KOiK04373.
OMAiPWITQKD.
OrthoDBiEOG091G05Z7.
PhylomeDBiQ15418.
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 (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q15418-1) [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
MPLAQLKEPW PLMELVPLDP ENGQTSGEEA GLQPSKDEGV LKEISITHHV 
        60         70         80         90        100
KAGSEKADPS HFELLKVLGQ GSFGKVFLVR KVTRPDSGHL YAMKVLKKAT 
       110        120        130        140        150
LKVRDRVRTK MERDILADVN HPFVVKLHYA FQTEGKLYLI LDFLRGGDLF 
       160        170        180        190        200
TRLSKEVMFT EEDVKFYLAE LALGLDHLHS LGIIYRDLKP ENILLDEEGH 
       210        220        230        240        250
IKLTDFGLSK EAIDHEKKAY SFCGTVEYMA PEVVNRQGHS HSADWWSYGV 
       260        270        280        290        300
LMFEMLTGSL PFQGKDRKET MTLILKAKLG MPQFLSTEAQ SLLRALFKRN 
       310        320        330        340        350
PANRLGSGPD GAEEIKRHVF YSTIDWNKLY RREIKPPFKP AVAQPDDTFY 
       360        370        380        390        400
FDTEFTSRTP KDSPGIPPSA GAHQLFRGFS FVATGLMEDD GKPRAPQAPL 
       410        420        430        440        450
HSVVQQLHGK NLVFSDGYVV KETIGVGSYS ECKRCVHKAT NMEYAVKVID 
       460        470        480        490        500
KSKRDPSEEI EILLRYGQHP NIITLKDVYD DGKHVYLVTE LMRGGELLDK 
       510        520        530        540        550
ILRQKFFSER EASFVLHTIG KTVEYLHSQG VVHRDLKPSN ILYVDESGNP 
       560        570        580        590        600
ECLRICDFGF AKQLRAENGL LMTPCYTANF VAPEVLKRQG YDEGCDIWSL 
       610        620        630        640        650
GILLYTMLAG YTPFANGPSD TPEEILTRIG SGKFTLSGGN WNTVSETAKD 
       660        670        680        690        700
LVSKMLHVDP HQRLTAKQVL QHPWVTQKDK LPQSQLSHQD LQLVKGAMAA 
       710        720        730 
TYSALNSSKP TPQLKPIESS ILAQRRVRKL PSTTL
Length:735
Mass (Da):82,723
Last modified:April 16, 2002 - v2
Checksum:i765731A4442A53DF
GO
Isoform 2 (identifier: Q15418-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-36: MPLAQLKEPW...GEEAGLQPSK → MEQDPKPPRL...GPGSGPQRDS

Show »
Length:744
Mass (Da):83,932
Checksum:i3121E64369EBDBBF
GO
Isoform 3 (identifier: Q15418-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-92: Missing.

Note: No experimental confirmation available.
Show »
Length:643
Mass (Da):72,698
Checksum:iB8362021FCCC17B5
GO
Isoform 4Curated (identifier: Q15418-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-35: MPLAQLKEPWPLMELVPLDPENGQTSGEEAGLQPS → MQTPADFPRVERDLVPCPR

Show »
Length:719
Mass (Da):81,147
Checksum:iD47F7EC9609D5ACF
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti609A → T in BAF85411 (PubMed:14702039).Curated1
Sequence conflicti619S → G in BAF85411 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_021864335K → T2 PublicationsCorresponds to variant dbSNP:rs2229712Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0415801 – 92Missing in isoform 3. 1 PublicationAdd BLAST92
Alternative sequenceiVSP_0413801 – 36MPLAQ…LQPSK → MEQDPKPPRLRLWALIPWLP RKQRPRISQTSLPVPGPGSG PQRDS in isoform 2. 1 PublicationAdd BLAST36
Alternative sequenceiVSP_0574691 – 35MPLAQ…GLQPS → MQTPADFPRVERDLVPCPR in isoform 4. Add BLAST35

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L07597 mRNA. Translation: AAC82497.1.
AK292722 mRNA. Translation: BAF85411.1.
AK299007 mRNA. Translation: BAH12926.1.
AK315730 mRNA. Translation: BAG38085.1.
AL109743 Genomic DNA. Translation: CAC36348.1.
AL627313 Genomic DNA. Translation: CAI14647.1.
AL627313 Genomic DNA. Translation: CAI14648.1.
AL627313 Genomic DNA. Translation: CAI14649.1.
CH471059 Genomic DNA. Translation: EAX07799.1.
BC014966 mRNA. Translation: AAH14966.1.
CCDSiCCDS284.1. [Q15418-1]
CCDS30649.1. [Q15418-2]
CCDS81286.1. [Q15418-4]
PIRiI51901.
RefSeqiNP_001006666.1. NM_001006665.1. [Q15418-2]
NP_001317370.1. NM_001330441.1. [Q15418-4]
NP_002944.2. NM_002953.3. [Q15418-1]
UniGeneiHs.149957.

Genome annotation databases

EnsembliENST00000374168; ENSP00000363283; ENSG00000117676. [Q15418-1]
ENST00000526792; ENSP00000431651; ENSG00000117676. [Q15418-3]
ENST00000530003; ENSP00000432281; ENSG00000117676. [Q15418-4]
ENST00000531382; ENSP00000435412; ENSG00000117676. [Q15418-2]
ENST00000628081; ENSP00000487553; ENSG00000281877. [Q15418-4]
ENST00000628256; ENSP00000487349; ENSG00000281877. [Q15418-2]
ENST00000629832; ENSP00000486881; ENSG00000281877. [Q15418-1]
ENST00000631108; ENSP00000487166; ENSG00000281877. [Q15418-3]
GeneIDi6195.
KEGGihsa:6195.
UCSCiuc001bmr.2. human. [Q15418-1]
uc057dso.1. human.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

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.

Entry informationi

Entry nameiKS6A1_HUMAN
AccessioniPrimary (citable) accession number: Q15418
Secondary accession number(s): A6NGG4
, A8K9K7, B2RDY8, B7Z5J0, E9PRI4, Q5SVM5, Q5SVM8, Q5SVM9, Q96C05, Q9BQK2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: April 16, 2002
Last modified: June 7, 2017
This is version 187 of the entry and version 2 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 1
    Human chromosome 1: 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