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Protein

Ribosomal protein S6 kinase beta-1

Gene

Rps6kb1

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the pre-initiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial RMP leading to dissociation of a RMP:PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at Thr-412, which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin. Phosphorylates and activates the pyrimidine biosynthesis enzyme CAD, downstream of MTOR (By similarity) (PubMed:8524831). Following activation by mTORC1, phosphorylates EPRS and thereby plays a key role in fatty acid uptake by adipocytes and also most probably in interferon-gamma-induced translation inhibition (PubMed:28178239).By similarity2 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.2 Publications

Activity regulationi

Activation requires multiple phosphorylation events on serine/threonine residues. Activation appears to be first mediated by phosphorylation of multiple sites in the autoinhibitory domain, which facilitates phosphorylation at Thr-412, disrupting the autoinhibitory mechanism and allowing phosphorylation of Thr-252 by PDPK1. The active conformation of the kinase is believed to be stabilized by a mechanism involving three conserved phosphorylation sites located in the kinase domain activation loop (Thr-252) and in the AGC-kinase C-terminal domain (Ser-394 in the middle of the tail/linker region and Thr-412 within a hydrophobic motif at its end). Activated by mTORC1; isoform Alpha I and isoform Alpha II are sensitive to rapamycin, which inhibits activating phosphorylation at Thr-412. Activated by PDPK1 (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei123ATPPROSITE-ProRule annotation1
Active sitei218Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi97 – 105ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: RGD
  • identical protein binding Source: IntAct
  • PDZ domain binding Source: RGD
  • peptide binding Source: RGD
  • protein kinase activity Source: RGD
  • protein phosphatase 2A binding Source: RGD
  • protein serine/threonine/tyrosine kinase activity Source: Ensembl
  • ribosomal protein S6 kinase activity Source: RGD

GO - Biological processi

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
Biological processApoptosis, Cell cycle, Translation regulation
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.11.1 5301
ReactomeiR-RNO-166208 mTORC1-mediated signalling
SABIO-RKiP67999

Names & Taxonomyi

Protein namesi
Recommended name:
Ribosomal protein S6 kinase beta-1 (EC:2.7.11.12 Publications)
Short name:
S6K-beta-1
Short name:
S6K1
Alternative name(s):
70 kDa ribosomal protein S6 kinase 1
Short name:
P70S6K1
Short name:
p70-S6K 1
Ribosomal protein S6 kinase I
p70 ribosomal S6 kinase alpha
Short name:
p70 S6 kinase alpha
Short name:
p70 S6K-alpha
Short name:
p70 S6KA
Gene namesi
Name:Rps6kb1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 10

Organism-specific databases

RGDi620683 Rps6kb1

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

Cell junction, Cytoplasm, Membrane, Mitochondrion, Mitochondrion outer membrane, Synapse, Synaptosome

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi28 – 32Missing : Almost complete loss of activity. 5
Mutagenesisi28F → A: Complete loss of activity. Abolishes interaction with RPTOR. Reduces phosphorylation. Loss of phosphorylation at T-412 and T-444. 2 Publications1
Mutagenesisi29D → A: Almost complete loss of activity; when associated with A-31. 1 Publication1
Mutagenesisi30I → A: Almost complete loss of activity; when associated with A-32. 1 Publication1
Mutagenesisi31D → A: Almost complete loss of activity; when associated with A-29. 1 Publication1
Mutagenesisi32L → A: Almost complete loss of activity; when associated with A-30. 1 Publication1
Mutagenesisi123K → M: Loss of activity towards ribosomal protein S6. 2 Publications1
Mutagenesisi123K → R: Loss of activity. 2 Publications1
Mutagenesisi252T → A: Loss of activity towards ribosomal protein S6 and reduced phosphorylation at Thr-412. 1 Publication1
Mutagenesisi256T → A: Loss of activity towards ribosomal protein S6 without effect on phosphorylation status. 1 Publication1
Mutagenesisi394S → A or D: Loss of activity towards ribosomal protein S6 and reduces phosphorylation at Thr-252. 1 Publication1
Mutagenesisi412T → A: Loss of activity towards ribosomal protein S6 and loss of phosphorylation at Thr-252. 1 Publication1
Mutagenesisi412T → E: Mimics phosphorylation. Constitutive active. No effect on activity towards ribosomal protein S6. 1 Publication1
Mutagenesisi434S → D: No effect on sensitivity to wortmannin and rapamycin; when associated with D-441, D-444 and D-447. 1 Publication1
Mutagenesisi441S → D: No effect on sensitivity to wortmannin and rapamycin; when associated with D-434, D-D-444 and D-447. 1 Publication1
Mutagenesisi444T → D: No effect on sensitivity to wortmannin and rapamycin; when associated with D-434, D-441, and D-447. 1 Publication1
Mutagenesisi447S → D: No effect on sensitivity to wortmannin and rapamycin; when associated with D-434, D-441 and D-444. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000243481 – 525Ribosomal protein S6 kinase beta-1Add BLAST525

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei252Phosphothreonine; by PDPK11 Publication1
Modified residuei394Phosphoserine1 Publication1
Modified residuei412Phosphothreonine; by MTOR, NEK6 and NEK73 Publications1
Modified residuei434Phosphoserine1 Publication1
Modified residuei441PhosphoserineBy similarity1
Modified residuei444Phosphothreonine1 Publication1
Modified residuei447PhosphoserineCombined sources1 Publication1
Modified residuei452PhosphoserineCombined sources1
Modified residuei516N6-acetyllysine1 Publication1

Post-translational modificationi

Dephosphorylation by PPP1CC at Thr-412 in mitochondrion (By similarity). Phosphorylation at Thr-412 is regulated by mTORC1. The phosphorylation at this site is maintained by an agonist-dependent autophosphorylation mechanism. Activated by phosphorylation at Thr-252 by PDPK1.By similarity3 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

PaxDbiP67999
PRIDEiP67999

PTM databases

iPTMnetiP67999
PhosphoSitePlusiP67999

Expressioni

Tissue specificityi

Brain.

Gene expression databases

BgeeiENSRNOG00000003919 Expressed in 10 organ(s), highest expression level in skeletal muscle tissue
GenevisibleiP67999 RN

Interactioni

Subunit structurei

Interacts with PPP1R9A/neurabin-1 (PubMed:9653190). Interacts with RPTOR (PubMed:11967149, PubMed:12604610). Interacts with IRS1 (By similarity). Interacts with EIF3B and EIF3C (By similarity). Interacts with POLDIP3 (By similarity). Interacts with TRAF4 (By similarity). Interacts (via N-terminus) with IER5 (By similarity).By similarity3 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi249866, 3 interactors
ELMiP67999
IntActiP67999, 6 interactors
MINTiP67999
STRINGi10116.ENSRNOP00000005226

Structurei

3D structure databases

ProteinModelPortaliP67999
SMRiP67999
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini91 – 352Protein kinasePROSITE-ProRule annotationAdd BLAST262
Domaini353 – 423AGC-kinase C-terminalAdd BLAST71

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni424 – 525Autoinhibitory domainAdd BLAST102

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi28 – 32TOS motif5

Domaini

The autoinhibitory domain is believed to block phosphorylation within the AGC-kinase C-terminal domain and the activation loop.
The TOS (TOR signaling) motif is essential for activation by mTORC1.

Sequence similaritiesi

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00920000148962
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiP67999
KOiK04688
OMAiENCMLNS
OrthoDBiEOG091G05Z7
PhylomeDBiP67999
TreeFamiTF313438

Family and domain databases

InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR011009 Kinase-like_dom_sf
IPR017892 Pkinase_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR016238 Ribosomal_S6_kinase
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
PF00433 Pkinase_C, 1 hit
PIRSFiPIRSF000605 Ribsml_S6_kin_1, 1 hit
SMARTiView protein in SMART
SM00133 S_TK_X, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS51285 AGC_KINASE_CTER, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket
Isoform Alpha I (identifier: P67999-1) [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
MRRRRRRDGF YPAPDFRHRE AEDMAGVFDI DLDQPEDAGS EDELEEGGQL
60 70 80 90 100
NESMDHGGVG PYELGMEHCE KFEISETSVN RGPEKIRPEC FELLRVLGKG
110 120 130 140 150
GYGKVFQVRK VTGANTGKIF AMKVLKKAMI VRNAKDTAHT KAERNILEEV
160 170 180 190 200
KHPFIVDLIY AFQTGGKLYL ILEYLSGGEL FMQLEREGIF MEDTACFYLA
210 220 230 240 250
EISMALGHLH QKGIIYRDLK PENIMLNHQG HVKLTDFGLC KESIHDGTVT
260 270 280 290 300
HTFCGTIEYM APEILMRSGH NRAVDWWSLG ALMYDMLTGA PPFTGENRKK
310 320 330 340 350
TIDKILKCKL NLPPYLTQEA RDLLKKLLKR NAASRLGAGP GDAGEVQAHP
360 370 380 390 400
FFRHINWEEL LARKVEPPFK PLLQSEEDVS QFDSKFTRQT PVDSPDDSTL
410 420 430 440 450
SESANQVFLG FTYVAPSVLE SVKEKFSFEP KIRSPRRFIG SPRTPVSPVK
460 470 480 490 500
FSPGDFWGRG ASASTANPQT PVEYPMETSG IEQMDVTTSG EASAPLPIRQ
510 520
PNSGPYKKQA FPMISKRPEH LRMNL
Length:525
Mass (Da):59,132
Last modified:October 11, 2004 - v1
Checksum:i013BA13EFB3508D7
GO
Isoform Alpha II (identifier: P67999-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-23: Missing.

Show »
Length:502
Mass (Da):56,159
Checksum:i00E6CF3FCAADDDB6
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti367P → R in AAA42104 (PubMed:2236064).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0188421 – 23Missing in isoform Alpha II. CuratedAdd BLAST23

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M58340 mRNA Translation: AAA42104.1
M57428 mRNA Translation: AAA42103.1
PIRiA36484 TVRTK6
RefSeqiNP_114191.1, NM_031985.1
UniGeneiRn.4042

Genome annotation databases

EnsembliENSRNOT00000005226; ENSRNOP00000005226; ENSRNOG00000003919 [P67999-1]
GeneIDi83840
KEGGirno:83840

Keywords - Coding sequence diversityi

Alternative initiation

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M58340 mRNA Translation: AAA42104.1
M57428 mRNA Translation: AAA42103.1
PIRiA36484 TVRTK6
RefSeqiNP_114191.1, NM_031985.1
UniGeneiRn.4042

3D structure databases

ProteinModelPortaliP67999
SMRiP67999
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi249866, 3 interactors
ELMiP67999
IntActiP67999, 6 interactors
MINTiP67999
STRINGi10116.ENSRNOP00000005226

PTM databases

iPTMnetiP67999
PhosphoSitePlusiP67999

Proteomic databases

PaxDbiP67999
PRIDEiP67999

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000005226; ENSRNOP00000005226; ENSRNOG00000003919 [P67999-1]
GeneIDi83840
KEGGirno:83840

Organism-specific databases

CTDi6198
RGDi620683 Rps6kb1

Phylogenomic databases

eggNOGiKOG0598 Eukaryota
ENOG410XNPH LUCA
GeneTreeiENSGT00920000148962
HOGENOMiHOG000233033
HOVERGENiHBG108317
InParanoidiP67999
KOiK04688
OMAiENCMLNS
OrthoDBiEOG091G05Z7
PhylomeDBiP67999
TreeFamiTF313438

Enzyme and pathway databases

BRENDAi2.7.11.1 5301
ReactomeiR-RNO-166208 mTORC1-mediated signalling
SABIO-RKiP67999

Miscellaneous databases

PROiPR:P67999

Gene expression databases

BgeeiENSRNOG00000003919 Expressed in 10 organ(s), highest expression level in skeletal muscle tissue
GenevisibleiP67999 RN

Family and domain databases

InterProiView protein in InterPro
IPR000961 AGC-kinase_C
IPR011009 Kinase-like_dom_sf
IPR017892 Pkinase_C
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR016238 Ribosomal_S6_kinase
IPR008271 Ser/Thr_kinase_AS
PfamiView protein in Pfam
PF00069 Pkinase, 1 hit
PF00433 Pkinase_C, 1 hit
PIRSFiPIRSF000605 Ribsml_S6_kin_1, 1 hit
SMARTiView protein in SMART
SM00133 S_TK_X, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS51285 AGC_KINASE_CTER, 1 hit
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiKS6B1_RAT
AccessioniPrimary (citable) accession number: P67999
Secondary accession number(s): P21425
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 11, 2004
Last sequence update: October 11, 2004
Last modified: September 12, 2018
This is version 140 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
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Main funding by: National Institutes of Health

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