RPS6KA1 (ribosomal protein S6 kinase, 90kDa, polypeptide 1)

2008-03-01   Philippe P Roux 

Institute for Research in Immunology, Cancer (IRIC), Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montreal QC H3C 3J7, Canada





RSK1 was the first cloned isoform of the p90 ribosomal S6 kinase family, which now contains three other members (RSK2, RSK3 and RSK4).


The genomic size of the entire RSK1 gene is about 45,260 bp and is located on the + strand of chromosome 1. This gene contains 22 coding exons.


The length of the transcript is 3,186 bp, from which the open reading frame contains 2,208 bp. While the 5UTR contains 154 bp, the 3UTR contains 824 bp.


No human pseudogene known.


Atlas Image
The RSK1 protein contains two kinase domains separated by a linker region of about 100 aa. While the N-terminal kinase domain (NTKD) belongs to the AGC family of kinases, the C-terminal kinase domain (CTKD) belongs to the CaMK family. RSK1 activation requires its interaction with ERK1 and ERK2 through its C-terminal ERK docking region, which initiates an ordered phosphorylation sequence leading to the phosphorylation of six serine or threonine residues (S221, T359, S363, S380, T573 and S732).


The RSK1 protein consists of 735 amino acids, with an apparent molecular weight of about 85-90 kDa.


Northern analyses and RNase protection assays revealed that RSK1 is expressed in many tissues, with higher levels in skeletal muscle, kidney, lung, liver, pancreas, spleen, thymus, and brain. Although other RSK isoforms are expressed ubiquitously in the brain, RSK1 is most abundant in the cerebellum. In situ hybridization of mouse embryonic tissues revealed that RSK1 is strongly expressed in regions harbouring highly proliferating cells. These include liver, lung, and thymus, as well as olfactory, respiratory, and gut epithelia.


RSK1 is normally present in the cytoplasm, but upon mitogenic stimulation it moves into the nucleus, where it phosphorylates several substrates involved in gene transcription. Within minutes of stimulation, RSK1 was shown to accumulate transiently at the plasma membrane, where it presumably receives additional inputs necessary for activation before nuclear translocation.


Mitogenic stimulation of the Ras/ERK pathway leads to the activation of RSK1. RSK1 seems to be a multifunctional ERK effector because it participates in various cellular processes, including nuclear signalling. RSK1 was found to regulate several transcription factors, including SRF, c-Fos, and Nur77. Additional nuclear factors have been shown to be regulated by RSK1, including MITF, estrogen receptor-a nuclear factor (NF)-ATc4 and ER81. RSK1 was shown to interact with the transcriptional coactivator CREB-binding protein (CBP), which, interestingly, binds many transcription factors known to be regulated by RSK1. On the basis of the nature of its substrates, RSK1 seems to have important functions in cellular growth control and proliferation. RSK1 may stimulate cell cycle progression through the regulation of immediate early gene products, such as c-Fos, which promotes the expression of cyclin D1 during the G0/G1 transition to S phase. Other proteins through which RSK1 may stimulate proliferation include the cyclin-dependent kinase (CDK) inhibitor p27kip1, the Na+/H+ exchanger NHE-1 and the kinase GSK3. RSK1 has been shown to phosphorylate and inhibit neuronal NO synthase in response to mitogenic signaling. RSK1 may also promote proliferation by regulating cell-growth-related protein synthesis. Indeed, RSK1 was shown to phosphorylate the tumour suppressor proteins TSC2 and LKB1, thereby resulting in increased mTOR signalling and mRNA translation.


The RSK family contains four human isoforms (RSK1, RSK2, RSK3 and RSK4), which share 65-73% aa identity. RSK-related molecules have also been identified in C. elegans (T01H8.1) and D. melanogaster (RPS6-protein kinase-II), which share around 50% aa identity to human RSK1 and also contain the two kinase domains typical to RSK family members. No RSK homologues have been found in yeast or plant.



The natural variant K335T has been observed.

Implicated in

Entity name
Various cancers
Frequent activation of the Ras/ERK signalling pathway has been reported in a broad range of human cancers including various carcinomas, glioblastomas and hematological malignancies. In some of these tumour types, RSK1 expression has been shown to be increased, such as in cancers of the breast and prostate.
Atlas Image
Hyperactivation of RSK has been reported in multiple cancers. Activation of growth factor receptors either by ligand stimulation or receptor overexpression/mutation are common mechanisms that lead to RSK activation. RSK is now known to be a central player in a signalling pathway consisting of many components that have been implicated in tumorigenesis, including upstream Ras GTPases and Raf kinases.
RSK1 is an important mediator of survival signals that protect cells from undergoing apoptosis and, thus, is a potentially important therapeutic target. Inhibition of RSK activity using the pharmacological inhibitor SL-0101 was shown to reduce the proliferation rates of breast cancer cells, but not normal breast epithelial cells.


Pubmed IDLast YearTitleAuthors
27795691989Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase.Alcorta DA et al
162138242005The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling.Anjum R et al
16483781991Distinct mechanisms for the activation of the RSK kinases/MAP2 kinase/pp90rsk and pp70-S6 kinase signaling systems are indicated by inhibition of protein synthesis.Blenis J et al
167383242006Subcellular localization and biological actions of activated RSK1 are determined by its interactions with subunits of cyclic AMP-dependent protein kinase.Chaturvedi D et al
15458231992Nuclear localization and regulation of erk- and rsk-encoded protein kinases.Chen RH et al
81320891993Cytoplasmic to nuclear signal transduction by mitogen-activated protein kinase and 90 kDa ribosomal S6 kinase.Chen RH et al
155399592005Phosphorylation of Cdc25C by pp90Rsk contributes to a G2 cell cycle arrest in Xenopus cycling egg extracts.Chun J et al
172599792007A clickable inhibitor reveals context-dependent autoactivation of p90 RSK.Cohen MS et al
159199952005Structural bioinformatics-based design of selective, irreversible kinase inhibitors.Cohen MS et al
94306881998Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/p90rsk that are inducible by MAPK.Dalby KN et al
82323151993Functional domains and phosphorylation of the orphan receptor Nur77.Davis IJ et al
158378012005p90Rsk is not involved in cytostatic factor arrest in mouse oocytes.Dumont J et al
39410811986Purification and characterization of a protein kinase from Xenopus eggs highly specific for ribosomal protein S6.Erikson E et al
86226651996Evidence for two catalytically active kinase domains in pp90rsk.Fisher TL et al
123747402002A phosphoserine/threonine-binding pocket in AGC kinases and PDK1 mediates activation by hydrophobic motif phosphorylation.Frödin M et al
108562372000A phosphoserine-regulated docking site in the protein kinase RSK2 that recruits and activates PDK1.Frödin M et al
145042892003Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization.Fujita N et al
104736401999A p90(rsk) mutant constitutively interacting with MAP kinase uncouples MAP kinase from p34(cdc2)/cyclin B activation in Xenopus oocytes.Gavin AC et al
92611391997The 90-kDa ribosomal S6 kinase (pp90rsk) phosphorylates the N-terminal regulatory domain of IkappaBalpha and stimulates its degradation in vitro.Ghoda L et al
168680292006RSK and MSK in MAP kinase signalling.Hauge C et al
158935972005Differential localization of MAPK-activated protein kinases RSK1 and MSK1 in mouse brain.Heffron D et al
82025121994Evidence that inactive p42 mitogen-activated protein kinase and inactive Rsk exist as a heterodimer in vivo.Hsiao KM et al
10480933199990-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1.Jensen CJ et al
95287691998pp90rsk1 regulates estrogen receptor-mediated transcription through phosphorylation of Ser-167.Joel PB et al
167635542006Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development.Kim M et al
81412491994Human rsk isoforms: cloning and characterization of tissue-specific expression.Moller DE et al
87567281996The signal-dependent coactivator CBP is a nuclear target for pp90RSK.Nakajima T et al
97246391998A link between MAP kinase and p34(cdc2)/cyclin B during oocyte maturation: p90(rsk) phosphorylates and inactivates the p34(cdc2) inhibitory kinase Myt1.Palmer A et al
155257592004The S6KII (rsk) gene of Drosophila melanogaster differentially affects an operant and a classical learning task.Putz G et al
166266232006The MAP kinase ERK5 binds to and phosphorylates p90 RSK.Ranganathan A et al
115859272001Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1.Richards SA et al
153429172004Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.Roux PP et al
151871872004ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions.Roux PP et al
128324672003Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Roux PP et al
173607042007RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation.Roux PP et al
170402102007BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo.Sapkota GP et al
92146311997IkappaB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase.Schouten GJ et al
112311482001Bub1 is activated by the protein kinase p90(Rsk) during Xenopus oocyte maturation.Schwab MS et al
167635662006The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity.Shahbazian D et al
106793222000Rsk1 mediates a MEK-MAP kinase cell survival signal.Shimamura A et al
99158261999Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo.Smith JA et al
169842262007p90 RSK-1 associates with and inhibits neuronal nitric oxide synthase.Song T et al
79010131993Phosphorylation and activation of human tyrosine hydroxylase in vitro by mitogen-activated protein (MAP) kinase and MAP-kinase-activated kinases 1 and 2.Sutherland C et al
104006371999p90(RSK) is a serum-stimulated Na+/H+ exchanger isoform-1 kinase. Regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1.Takahashi E et al
91992051997Identification of serine 380 as the major site of autophosphorylation of Xenopus pp90rsk.Vik TA et al
115003642001Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase.Wang X et al
162233622006Nur77 is phosphorylated in cells by RSK in response to mitogenic stimulation.Wingate AD et al
150240892004Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site.Woo MS et al
156574202005Recruitment of the extracellular signal-regulated kinase/ribosomal S6 kinase signaling pathway to the NFATc4 transcription activation complex.Yang TT et al
89399141996Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases.Zhao Y et al

Other Information

Locus ID:

NCBI: 6195
MIM: 601684
HGNC: 10430
Ensembl: ENSG00000117676


dbSNP: 6195
ClinVar: 6195
TCGA: ENSG00000117676


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
mTOR signaling pathwayKEGGko04150
Long-term potentiationKEGGko04720
Progesterone-mediated oocyte maturationKEGGko04914
MAPK signaling pathwayKEGGhsa04010
mTOR signaling pathwayKEGGhsa04150
Long-term potentiationKEGGhsa04720
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Progesterone-mediated oocyte maturationKEGGhsa04914
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
Neuronal SystemREACTOMER-HSA-112316
Transmission across Chemical SynapsesREACTOMER-HSA-112315
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic CellREACTOMER-HSA-112314
Activation of NMDA receptor upon glutamate binding and postsynaptic eventsREACTOMER-HSA-442755
Post NMDA receptor activation eventsREACTOMER-HSA-438064
CREB phosphorylation through the activation of RasREACTOMER-HSA-442742
RSK activationREACTOMER-HSA-444257
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
CREB phosphorylationREACTOMER-HSA-199920
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Nuclear Events (kinase and transcription factor activation)REACTOMER-HSA-198725
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
L1CAM interactionsREACTOMER-HSA-373760
Recycling pathway of L1REACTOMER-HSA-437239
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
Insulin resistanceKEGGhsa04931

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
120800862002Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.384
187221212008Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation.138
159051732005Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase.122
197167942009RSK is a principal effector of the RAS-ERK pathway for eliciting a coordinate promotile/invasive gene program and phenotype in epithelial cells.89
191504322009betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis.86
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
156473512005Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors.72
194704702009RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility.66
119143782002Regulation of an activated S6 kinase 1 variant reveals a novel mammalian target of rapamycin phosphorylation site.54
162138242005The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling.46


Philippe P Roux

RPS6KA1 (ribosomal protein S6 kinase, 90kDa, polypeptide 1)

Atlas Genet Cytogenet Oncol Haematol. 2008-03-01

Online version: http://atlasgeneticsoncology.org/gene/43477/rps6ka1-(ribosomal-protein-s6-kinase-90kda-polypeptide-1)