| 1993 |
ERK2/MAP kinase directly phosphorylates RSK1 in vitro, increasing its 40S ribosomal and peptide kinase activity, retarding its SDS-PAGE migration, and generating new autophosphorylation sites. Activation state correlates with phosphorylation by ERK2, and PP2A dephosphorylation reverses activation. |
In vitro kinase assay with purified ERK2, phosphopeptide mapping, PP2A dephosphorylation, epitope-tagged RSK1 expressed in COS cells |
Biochemistry |
High |
7688567
|
| 1995 |
The N-terminal kinase domain of RSK1 mediates substrate phosphorylation, while the C-terminal kinase domain is required for full activation of the N-terminal domain. MAPK phosphorylation site T570 (C-domain) is not required for growth factor-stimulated autophosphorylation or kinase activation. Both domains contribute to autophosphorylation. |
Site-directed mutagenesis of kinase-dead and phosphorylation-site mutants of human RSK3 (p90rsk), expressed in COS cells, immune complex kinase assays |
The Journal of biological chemistry |
High |
7642538
|
| 1998 |
Six regulatory phosphorylation sites in MAPKAP-K1a/p90rsk are identified: Ser222 and Ser733 are phosphorylated basally; PMA induces phosphorylation of Thr360, Ser364, Thr574, and Ser381. ERK/MAPK activates the C-terminal kinase domain by phosphorylating Thr574 and contributes to N-terminal domain activation by phosphorylating Ser364. The activated C-terminal domain then autophosphorylates Ser381, which together with Ser364 phosphorylation activates the N-terminal kinase domain. |
Phosphopeptide mapping and site-directed mutagenesis in transfected COS-1 cells, in vitro kinase assays |
The Journal of biological chemistry |
High |
9430688
|
| 1999 |
RSK1 is phosphorylated by PDK1 within the amino-terminal kinase-activation loop and by ERK in the carboxy-terminal kinase-activation loop. Full activation of RSK1 in vivo requires both PDK1 and ERK; neither alone is sufficient for full-length RSK1 activation. |
In vitro kinase assays with purified ERK and PDK1 on isolated RSK1 kinase domains, transfection of HEK 293E cells, PDK1-dependent phosphorylation assays |
Current biology : CB |
High |
10469565
|
| 1999 |
RSK1 directly phosphorylates the pro-apoptotic protein BAD at Ser112 and Ser136 both in vitro and in vivo, promoting BAD/14-3-3 binding and abrogating BAD's pro-apoptotic function. A constitutively active RSK1 allele promotes cell survival; kinase-dead RSK1 blocks MEK-dependent survival signaling. |
In vitro kinase assay, in vivo phosphorylation in IL-3-dependent cells, constitutively active and kinase-dead RSK1 mutants, cell survival assays |
Current biology : CB |
High |
10679322
|
| 1999 |
p90RSK phosphorylates BAD at Ser112 in vitro and in vivo in a PKC-dependent pathway, stimulates BAD/14-3-3 binding, and blocks BAD-mediated apoptosis in a Ser112-dependent manner. PKC isoforms tested could not directly phosphorylate BAD, indicating RSK acts as a downstream Bad kinase. |
In vitro kinase assay, phorbol ester stimulation in cells, PKC inhibitors, 14-3-3 co-immunoprecipitation, cell death assays |
The Journal of biological chemistry |
High |
10574959
|
| 1999 |
Expression of a constitutively active form of p90Rsk in Xenopus embryos induces cleavage arrest with metaphase spindles characteristic of meiotic metaphase, demonstrating that p90Rsk is a mediator of MAPK-dependent cytostatic factor (CSF) arrest. |
Expression of constitutively active Rsk in Xenopus embryos, cytological analysis of arrested blastomeres |
Science (New York, N.Y.) |
High |
10558992
|
| 2001 |
p90RSK1 and p70 S6 kinase both phosphorylate eEF2 kinase at a conserved serine residue in vitro and inhibit its activity. In response to stimuli that activate ERK (but not mTOR), regulation of eEF2 phosphorylation is blocked by MEK/ERK inhibitors but not rapamycin, consistent with p90RSK1 as the relevant kinase. Regulation of eEF2 requires PDK1. |
In vitro phosphorylation of eEF2 kinase by recombinant p90RSK1 and p70S6K; rapamycin and MEK inhibitor pharmacology; PDK1 knockout cells |
The EMBO journal |
High |
11500364
|
| 2001 |
p90Rsk phosphorylates Xenopus Bub1 in vitro and increases its protein kinase activity; injection of constitutively active p90Rsk restores Bub1 activation in MEK-inhibitor-treated oocytes. Bub1 is thus a downstream effector of p90Rsk in meiotic CSF arrest. |
In vitro kinase assay with purified p90Rsk and Bub1, constitutively active Rsk injection into oocytes with MEK inhibitor U0126, immune complex kinase assays |
Current biology : CB |
High |
11231148
|
| 2001 |
UVA induces phosphorylation of p90RSK at Ser381 via both ERK and JNK pathways. ERK2 and JNK2 (but not p38 kinase) immunoprecipitate with p90RSK after UVA stimulation and phosphorylate p90RSK in vitro. JNK1/2 knockout cells show markedly attenuated p90RSK phosphorylation. |
Co-immunoprecipitation, dominant-negative kinase mutants, JNK1/2-null cells, pharmacological inhibitors, in vitro kinase assays |
The Journal of biological chemistry |
High |
11278279
|
| 2001 |
MEK, ERK, and RSK1/2/3 are enriched on mitotic spindle and midbody tubulin in dividing Swiss 3T3 cells. MEK inhibition prevents mitotic exit and alters CDK activities, indicating the MAP kinase pathway coordinates passage through mitosis via RSK. |
Subcellular fractionation, immunofluorescence of mitotic cells, MEK inhibitor treatment, CDK activity assays |
Cellular signalling |
Medium |
11495723
|
| 2004 |
Constitutively active RSK1 (but not RSK2) induces neurite outgrowth and differentiation of PC12 cells in the absence of NGF, without activating the endogenous MAPK pathway. PDK1-binding site mutations abolish this activity, indicating RSK1 is sufficient and the only MAPK target required for NGF-induced differentiation. |
Transient expression of constitutively active RSK1/RSK2 mutants in PC12 cells, neurite outgrowth assay, PDK1-binding site mutagenesis |
Molecular and cellular biology |
High |
15572664
|
| 2005 |
p90Rsk is not required for MII cytostatic factor arrest in mouse oocytes. Constitutively active Rsk1 and Rsk2 do not restore MII arrest in mos-/- oocytes, and triple Rsk1/2/3 knockout oocytes show normal CSF arrest. This contrasts with the requirement seen in Xenopus. |
Injection of constitutively active Rsk1/Rsk2 into mos-/- oocytes and two-cell embryos; triple RSK knockout mouse oocytes |
The Journal of cell biology |
High |
15837801
|
| 2006 |
Inactive RSK1 interacts with the type I regulatory subunit (RI) of PKA, while active RSK1 interacts with the PKA catalytic subunit (PKAc). These interactions modulate PKA activity (active RSK1 reduces cAMP responsiveness) and determine RSK1 subcellular localization via AKAPs: disrupting AKAP interactions reduces nuclear accumulation of active RSK1, increasing phosphorylation of cytosolic substrates TSC2 and BAD. |
Co-immunoprecipitation, subcellular fractionation, dominant-negative AKAP disruption, phosphorylation assays for TSC2 and BAD |
Molecular and cellular biology |
High |
16738324
|
| 2006 |
p90Rsk is required for G1-phase arrest in unfertilized starfish eggs downstream of the Mos-MAPK pathway. Inhibition of Rsk with a neutralizing antibody releases G1 arrest and initiates DNA replication; constitutively active Rsk prevents DNA replication after fertilization. |
Neutralizing antibody injection, constitutively active Rsk injection into starfish oocytes/eggs, DNA replication assays |
Development (Cambridge, England) |
High |
16571626
|
| 2006 |
IGF-I stimulates p90Rsk activity, which directly phosphorylates Hsp27 in vitro and in vivo. Inhibition of p90Rsk (siRNA or dominant-negative mutant) abolishes IGF-I-induced Hsp27 phosphorylation, and Hsp27 knockdown destabilizes Bad/14-3-3 complexes and increases apoptosis. |
In vitro kinase assay, siRNA, dominant-negative p90Rsk, co-immunoprecipitation of Bad/14-3-3 |
Cancer research |
Medium |
20197463
|
| 2007 |
In Xenopus eggs, Erp1/Emi2 (an APC/C inhibitor) is a direct substrate of p90rsk. Mos-dependent phosphorylation of Erp1 by p90rsk at Thr336, Ser342, and Ser344 stabilizes Erp1 and establishes CSF arrest in meiosis II. Phosphorylation also enhances Erp1 binding to APC/C at its C-terminal destruction box. |
In vitro phosphorylation, phosphosite mutagenesis, Xenopus egg extract and oocyte injection experiments, semi-quantitative biochemical analysis |
Nature |
High |
17410129
|
| 2007 |
Crystal structures of the unactivated RSK1 N-terminal kinase domain (NTKD) bound to three different ligands resolved at 2.0 Å. The activation loop and helix αC are disordered in the inactive state; the DFG motif adopts an 'active-like' conformation; and the β-phosphate group in the AMP-PCP complex adopts a unique conformation contributing to inactivity. |
X-ray crystallography at 2.0 Å resolution |
Protein science : a publication of the Protein Society |
High |
17965187
|
| 2009 |
RSK1 phosphorylates p27Kip1 at T198, promoting p27 cytoplasmic mislocalization, p27-RhoA binding, RhoA-GTP reduction, loss of actin stress fibers, and increased cell motility. RSK1 co-precipitates with p27 in cells; siRNA to RSK1 rapidly reduces p27pT198; T198-phosphorylated p27 shows increased RhoA binding in vitro. |
siRNA knockdown, RSK1 overexpression, in vitro kinase assay, co-immunoprecipitation, RhoA-GTP pull-down, cell motility assay |
Proceedings of the National Academy of Sciences of the United States of America |
High |
19470470
|
| 2009 |
In response to survival signals, Rsk1/2 phosphorylate BimEL on three serine residues in a conserved degron, facilitating binding to βTrCP F-box protein and subsequent proteasomal degradation of BimEL. Erk1/2-mediated phosphorylation of BimEL at Ser69 promotes this Rsk1/2-dependent degron phosphorylation. BimEL phosphorylation mutants unable to bind βTrCP are stabilized and more pro-apoptotic. |
Phosphorylation site mutagenesis, co-immunoprecipitation of BimEL with βTrCP, siRNA knockdown of Rsk1/2 and βTrCP, apoptosis assays in NSCLC cells |
Molecular cell |
High |
19150432
|
| 2010 |
RSK1 phosphorylates VASP at T278 (a site regulating actin binding) as identified by co-immunoprecipitation and kinase assay. RSK1 silencing increases lung cancer cell metastatic potential in a zebrafish model. |
Kinome-wide siRNA screen, co-immunoprecipitation of RSK1 with VASP and Mena, in vitro phosphorylation of VASP at T278, zebrafish invasion model |
Oncogene |
Medium |
21423205
|
| 2011 |
Keratin 17 (K17) Ser44 is phosphorylated by RSK1 in skin keratinocytes in response to growth stimuli (serum, EGF, TPA) and cellular stresses. The RSK1 consensus phosphorylation sequence surrounds K17-Ser44, and RSK1 directly phosphorylates this site. |
In vitro kinase assay, phospho-specific antibody, mass spectrometry identification, cellular stimulation experiments |
The Journal of biological chemistry |
Medium |
22006917
|
| 2011 |
Hypoxia activates p90RSK, which phosphorylates NHE-1, leading to increased Na+/H+ exchange and invadopodia formation in cancer cells. p90RSK inhibition or shRNA depletion blocks hypoxia-induced invadopodia and invasion. |
shRNA depletion of NHE-1 and p90RSK, intracellular pH live-cell imaging, invasion assays |
PloS one |
Medium |
22216126
|
| 2012 |
p90RSK associates with ERK5 and directly phosphorylates ERK5 at S496, inhibiting ERK5 transcriptional activity and upregulating VCAM-1 expression while reducing eNOS. p90RSK and CHIP compete for ERK5 binding at aa571–807; p90RSK activation inhibits ERK5/CHIP association and CHIP ubiquitin ligase activity, increasing ICER levels and promoting cardiac apoptosis. |
Co-immunoprecipitation, in vitro phosphorylation of ERK5 S496, ERK5 S496A mutant, dominant-negative p90RSK overexpression, cardiac-specific ERK5 deletion, myocardial infarction mouse model |
Circulation research |
High |
22267842
|
| 2012 |
p90RSK also inhibits ERK5 transcriptional activity in endothelial cells by associating with ERK5 and phosphorylating ERK5 S496, upregulating VCAM-1 and reducing eNOS. EC-specific ERK5 knockout increases leukocyte rolling; p90RSK inhibition ameliorates EC dysfunction in diabetic mice via ERK5. |
Inducible EC-specific ERK5 knockout mice, p90RSK inhibitor FMK-MEA, VCAM-1 and eNOS expression, co-immunoprecipitation |
Circulation |
High |
23243209
|
| 2005 |
p90RSK directly phosphorylates cardiac troponin I (cTnI) at Ser23/Ser24 in vitro with high substrate affinity (but not cardiac troponin T). Dominant-negative p90RSK prevents H2O2-mediated cTnI phosphorylation in cardiomyocytes; cardiac-specific p90RSK transgenic mice show increased cTnI Ser23/Ser24 phosphorylation. |
In vitro kinase assay, adenovirus-dominant-negative p90RSK, cardiac-specific p90RSK transgenic mice, phospho-specific antibodies |
The Journal of biological chemistry |
High |
15840586
|
| 2015 |
Crystal structure of an RSK1 construct in complex with its activator kinase ERK2 is determined; the structure captures a precatalytic state where the RSK1 activation loop faces ERK2's catalytic site. The MAPK-binding linear motif in the disordered RSK1 C-terminal extension binds the ERK2 docking groove to form an encounter complex, and generic kinase domain contacts bring them into a catalytically competent state. |
X-ray crystallography, molecular dynamics simulation, biochemical and cellular MAPK→MAPKAPK signaling assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
25730857
|
| 2015 |
S100B inhibits RSK1 by Ca2+-dependent binding to the CaMK-type (C-terminal) kinase domain of RSK1. Crystallographic, SAXS, and NMR analysis reveal that S100B forms a 'fuzzy' complex with RSK1 peptide ligands; binding involves both conformational selection and induced-fit steps. |
X-ray crystallography, SAXS, NMR, fast-kinetics experiments, in vitro biochemical characterization |
The Journal of biological chemistry |
High |
26527685
|
| 2015 |
Disturbed flow activates p90RSK, which phosphorylates SENP2 at Thr368, promoting SENP2 nuclear export and reducing SENP2 function. This leads to increased SUMOylation of p53 and ERK5, downregulation of eNOS, upregulation of adhesion molecules and apoptosis, and accelerated atherosclerosis. |
In vitro phosphorylation of SENP2 T368, dominant-negative p90RSK mouse model (EC-specific overexpression), SENP2 knockdown, LDLR-KO atherosclerosis model |
The Journal of clinical investigation |
High |
25689261
|
| 2006 |
IGF-I/MAPK/p90Rsk signaling promotes nuclear export of Hdm2; constitutively active p90Rsk drives cytoplasmic accumulation of Hdm2 and reduces p53 activity. Constitutively active p90Rsk cooperates with E1A, oncogenic H-Ras, and hTERT to transform normal human fibroblasts (anchorage-independent growth). |
Dominant-negative and constitutively active p90Rsk expression, Hdm2/p53 nuclear/cytoplasmic fractionation, anchorage-independent growth assay with multiple oncogenes |
The Journal of biological chemistry |
Medium |
16621805
|
| 2010 |
IFNλ activates RSK1 and its downstream effector eIF4B. Prior to IFNλ stimulation, non-active RSK1 is present in a complex with the translational repressor 4E-BP1. IFNλ-induced RSK1 activation causes RSK1 dissociation from 4E-BP1 and allows eIF4F formation and cap-dependent translation; RSK1 is essential for up-regulation of p21WAF1/CIP1. |
Co-immunoprecipitation of RSK1 with 4E-BP1 and eIF4B, siRNA knockdown of RSK1, IFNλ stimulation assays, p21 expression analysis |
The Journal of biological chemistry |
Medium |
21075852
|
| 2009 |
p90RSK phosphorylates NHE1 at Ser703 in adipocytes in response to insulin. RSK1 N-terminal kinase domain inhibitors (BI-D1870, SL0101) block both NHE1 Ser703 phosphorylation and insulin-stimulated glucose uptake, while ERK1/2 inhibition blocks NHE1 phosphorylation but not glucose uptake. |
Pharmacological inhibitors selective for RSK N-terminal vs C-terminal domains, phospho-specific antibodies, glucose uptake assays, GLUT4 translocation assays in 3T3-L1 adipocytes |
Cellular signalling |
Medium |
19765648
|
| 2010 |
TGFβ activates eEF2 (decreases eEF2 phosphorylation) and inactivates eEF2 kinase via an ERK1/2-dependent increase in p90Rsk phosphorylation. A dominant-negative p90Rsk reverses TGFβ-induced changes in eEF2/eEF2 kinase phosphorylation and significantly attenuates TGFβ-induced protein synthesis and hypertrophy of mesangial cells. |
Dominant-negative p90Rsk expression, ERK1/2 inhibition, eEF2 and eEF2 kinase phosphorylation assays, protein synthesis and hypertrophy measurements |
FEBS letters |
Medium |
20837011
|
| 2011 |
RSK1 phosphorylates UBE2R1 (a ubiquitin-conjugating enzyme) at Thr162. Phosphorylation of UBE2R1-T162 promotes its self-ubiquitination and destabilization, reducing UBE2R1-mediated P-glycoprotein (ABCB1) ubiquitination and thereby protecting P-gp from proteasomal degradation. T162D (phosphomimetic) UBE2R1 fails to ubiquitinate P-gp. |
In vitro kinase assay of RSK1 on UBE2R1, phosphomimetic/alanine mutants, ubiquitination assays, P-gp expression and drug sensitivity assays |
Scientific reports |
High |
27786305
|
| 2008 |
ERK-RSK1 (but not RSK2) activation by growth factors at G2 phase delays G2/M transition in HeLa cells, delays cyclin B1-associated kinase activation and nuclear translocation of cyclin B1, and reduces chromosomal segregation defects. siRNA knockdown specifically of RSK1 (not RSK2) abrogates the G2/M delay. |
siRNA knockdown of RSK1 vs RSK2, FACS, mitotic index, time-lapse microscopy, cyclin B1 kinase and localization assays |
Cellular signalling |
Medium |
18450423
|
| 1998 |
Metabotropic glutamate receptor stimulation in hippocampal slices induces a rapid PKC-dependent translocation of p90rsk to polyribosomes, with concomitant enhanced phosphorylation of at least six polyribosome-binding proteins. Both ERK-2 (the p90rsk-activating kinase) and glycogen synthase kinase 3β (a known p90rsk substrate) are present on polyribosomes. |
Subcellular fractionation of hippocampal slices, immunoblotting, PKC inhibition, metabotropic glutamate receptor stimulation |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
9844018
|
| 2021 |
In pancreatic cancer, RSK1 selectively interacts with membrane-bound mutant KRASG12D (identified by proximity labeling/BioID mass spectrometry). This interaction requires NF1 and SPRED2. Membrane RSK1 mediates negative feedback on wild-type RAS signaling and impedes pancreatic cancer cell proliferation upon ablation of mutant KRAS. |
BioID proximity labeling, mass spectrometry, co-immunoprecipitation, RSK1 ablation studies in murine PDAC cells |
Proceedings of the National Academy of Sciences of the United States of America |
Medium |
34021083
|
| 2019 |
FLT3-ITD activates RSK1/2 through MEK/ERK and PDK1 pathways. RSK1 phosphorylates S6RP at S235/S236, TSC2 at S1798, eIF4B at S422 (and cooperatively at S406 with PIM), thereby activating mTORC1/S6K/4EBP1 and eIF4B to promote cap-dependent translation. RSK1 also phosphorylates Bad at S75 and downregulates BIM-EL cooperatively with ERK. |
Phospho-specific antibodies, RSK inhibitors (BI-D1870), siRNA knockdown, FLT3-ITD cell lines, proliferation/apoptosis assays |
Cancers |
Medium |
31756944
|
| 2022 |
IL11-stimulated ERK/P90RSK activity causes phosphorylation of LKB1 at S325 and S428, leading to LKB1 inactivation, AMPK inhibition, and mTOR activation across stromal, epithelial, and hepatocyte cell types. This drives myofibroblast transformation, SNAI1 expression, and epithelial dysfunction. |
Phospho-specific antibodies for LKB1, AMPK, mTOR; pharmacological ERK inhibition; genetic manipulation of IL11 signaling in mice |
iScience |
Medium |
35992082
|
| 2022 |
RSK1 is required for axon regeneration in dorsal root ganglion neurons after sciatic nerve injury. Mechanistically, RSK1 preferentially regulates the synthesis of regeneration-related proteins (identified by ribosomal profiling). RSK1 expression is upregulated in injured DRG but not retinal ganglion cells; RSK1 overexpression enhances PTEN-deletion-induced axon regeneration in the CNS. |
Chemical inhibitor screening, gain- and loss-of-function analyses, ribosomal profiling, sciatic nerve injury model, retinal ganglion cell CNS model |
PLoS biology |
Medium |
35648763
|
| 2010 |
The YopM effector of Yersinia binds RSK1 through its C-terminal domain (from LRR12 to C-terminus); this interaction domain is distinct from the LRR6–LRR15 region required for PRK2 binding. Both RSK1 and PRK2 interaction domains of YopM are required for IL-10 induction in vivo and for virulence, establishing RSK1 as a host kinase exploited by a bacterial pathogen. |
In vitro binding assays with YopM truncation mutants, co-immunoprecipitation, murine infection models |
Infection and immunity |
Medium |
20515922
|