Expression data from U251 RSK1 Knockout and RSK2 Knockout cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE213592 | GEO | 2022/09/19
REPOSITORIES: GEO
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Project description:The p90 ribosomal S6 kinase (RSK) family, downstream targets of Ras/ERK signaling, encompass four human isoforms (RSK1-4). Glioblastoma (GBM) predominantly expresses RSK1 and RSK2. Notably, RSK1 is markedly upregulated in a subset of GBMs associated with dismal prognosis and immune infiltration, whereas RSK2 expression remains consistent across cases. We verified that GBM-derived cell lines recapitulate RSK isoform expression profiles and estimated their stoichiometry. Through the generation of RSK1 and RSK2 knockout (RSK1KO and RSK2KO) as well as double knockout (DKO) GBM cells, we investigated isoform-specific functions of RSK. Surprisingly, contrary to conventional belief, we found that mTORC1 is not activated by RSK isoforms. Instead, eIF4B phosphorylation at S422 was RSK-dependent rather than mTORC1/S6K-dependent, with RSK1 exerting a more pronounced effect. Intriguingly, RSK1 and RSK2 displayed differential effects on translation, with RSK1 maintaining translation of specific mRNAs under conditions of reduced overall translation due to mTORC1 inhibition, unlike RSK2. Finally, we verified that while the translatome of RSK1KO cells show a downregulation of mRNAs affecting cell cycle, DNA replication and repair, RSK2 depletion impacted mitochondrial and respiratory genes. Notably, DKO cells exhibited compounded phenotypes, underscoring the existence of isoform-specific gene regulation programs orchestrated by RSK. Collectively, our findings offer mechanistic insights crucial for unraveling the role of RSK1 in GBMs.
2025-06-25 | GSE263893 | GEO
Project description:RSK1 and RSK4 are two of the four members of the p90 ribosomal protein S6 kinases (RSK) family. These kinases are downstream kinases of mitogen-activated protein kinase 1 (ERK or MAPK1) in the ERK MAP kinase pathway. RSKs are implicated in fine tuning of cellular processes such as translation, transcription, proliferation, and motility. Previous work showed that pathogens such as Cardioviruses could hijack any of the four RSK isoforms to inhibit PKR activation or to disrupt cellular nucleocytoplasmic trafficking. In contrast, some reports suggest non-redundant functions for distinct RSK isoforms and Coffin-Lowry syndrome has only been associated with mutations in the gene encoding RSK2. In this work, we used the analog-sensitive kinase strategy to ask whether the cellular substrates of distinct RSK isoforms differ. We therefore compared the substrates of 2 of the most distant RSK isoforms: RSK1 and RSK4. We identified a series of potential substrates for both RSKs in cells, and validated RanBP3, PDCD4, IRS2 and ZC3H11A as substrates of both RSK1 and RSK4, and SORBS2 as a RSK1 substrate. In addition, using mutagenesis and inhibitors, we confirmed analog-sensitive kinase data showing that endogenous RSKs phosphorylate TRIM33 at S1119. Our data thus identify a series of potential RSK substrates and suggest that the substrates of RSK1 and RSK4 largely overlap and that the specificity of the various RSK isoforms likely depends on their cell- or tissue-specific expression pattern.
2024-02-06 | PXD047020 | Pride
Project description:The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase (ERK) signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 (mTORC1) pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in non-tumoral brain (NB) and grade I-IV gliomas. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBMs demonstrating the lowest RSK3 protein levels. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (RSK1hi) that excluded long-survivor cases expressed higher levels of RSK1. No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in glioblastomas (GBM) were associated with worse survival. RSK1hi and, to a lesser extent, RSK2hi GBMs, showed higher levels of phosphorylated RSK, which indicates RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated-natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long-survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker LAPTM5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform-specific peculiarities. The progression-dependent expression and association with immune infiltration, suggests RSK1 as a potential progression marker and therapeutic target for gliomas.
2019-10-26 | GSE139380 | GEO
Project description:Expression data from U251 RSK1 Knockout and RSK2 Knockout cell lines
| PRJNA881724 | ENA
Project description:The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked monogenic disease associating severe learning deficit andassociated to typical facial and digital abnormalities and skeletal changes. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized. In this study we explore, through X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, an animal model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report in these mutants the occurrence of a surpernumerary tooth mesial to the first molar. This highly penetrant phenotype is considered as a remnant of evolutionary lost teeth. This possibly leads to the significant reduction of the maxillary diastema. Abnormalities of molar shape were almost restricted to the mesial part of both upper and lower first molars (M1). We also report an expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) at various stages of odontogenesis in wild-type (WT) mice. Rsk2 was mainly expressed in the mesenchymal, neural crest derived compartment, correlating with proliferative areas of the developing teeth and consistent with a biological function of RSK2 in cell cycle control and cell growth, which when invalidated could be responsible for the dental phenotype. In an attempt to unravel the molecular pathways involved in the genesis of these dental defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars, and further demonstrated a misregulation of selected genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro.
2014-01-13 | E-GEOD-51034 | biostudies-arrayexpress
Project description:Proteins from unrelated pathogens, including some RNA or DNA viruses and bacteria can recruit and activate cellular p90-ribosomal protein S6 kinases (RSKs) through a common linear motif. Data suggested a model where pathogens' proteins act to dock the recruited RSKs toward specific substrates, which then act as effectors to the benefit of the pathogens. Using cardiovirus leader protein (L) as a paradigm, we show that pathogens' proteins can modify the spectrum of RSK substrates in infected cells. L triggers nucleocytoplasmic trafficking perturbation and phenylalanine-glycine (FG)-nucleoporin hyperphosphorylation in an RSK-dependent fashion. Biotin ligase experiments identified FG-nucleoporins as common partners of L and RSK in infected cells. Using cells expressing an analog-sensitive RSK2 mutant, we show that L triggers direct phosphorylation of NUP98 and NUP214 by RSK2 in infected cells. Our data therefore demonstrate a novel virulence mechanism where pathogens' proteins hijack and retarget cellular protein kinases of the RSK family
2022-12-08 | PXD034604 | Pride
Project description:Deregulated cell migration and invasion, which are hallmarks of metastatic cancer cells, are correlated to structural and functional alterations of the actin cytoskeleton associated to a large panel of actin-binding proteins. Among these, the actin-bundling protein L-plastin, initially detected in leukocytes, is ectopically expressed in several solid tumours and is often considered as a metastatic marker. Phosphorylation of L-plastin on residue serine 5 (Ser5) has been shown to activate L-plastin and to be crucial for invasion and metastasis formation. Here, we investigate the signalling pathway leading to L-plastin Ser5 phosphorylation in four breast cancer cell lines. Whole genome microarray analysis comparing cell lines with different invasive capacities and corresponding L-plastin Ser5 phosphorylation levels revealed that genes of the MAPK/ERK pathway are differentially expressed. In line, in vitro kinase assays showed that MAPK/ERK pathway downstream kinases RSK1 and RSK2 are able to directly phosphorylate L-plastin on Ser5. In parallel to a knockdown approach, activation and inhibition studies of signalling molecules of the MAPK/ERK pathway, followed by computational modelling analysis, confirmed that RSK is an important activator of L-plastin in all four studied cell lines. Finally and rounding up our study, RSK knockdown significantly impaired migratory and invasive capacities of a selected invasive cell line, thus consolidating RSK as a promising therapeutic target in certain invasive carcinomas. Altogether, our data provide substantial evidence that the MAPK/ERK pathway is involved in L-plastin Ser5 phosphorylation in breast cancer cells with its downstream kinases RSK1 and RSK2 being able to directly phosphorylate L-plastin on Ser5.
2016-03-26 | E-MTAB-3487 | biostudies-arrayexpress
Project description:Hydrogen deuterium exchange mass spectrometry data of the ERK2-RSK2 and ERK2-RSK2-ORF45 complexes. The noncatalytic viral protein ORF45 reconfigures ERK-RSK signaling in cells. This dataset identifies the ORF45-RSK2 interface.
2021-12-22 | MSV000088607 | MassIVE
Project description:Influenza viruses (IV) exploit a variety of signaling pathways. Previous studies showed that the Raf/MEK/ERK pathway is functionally linked to nuclear export of viral ribonucleoprotein (vRNP) complexes, suggesting that vRNP export is a signaling induced event. However, the underlying mechanism remained completely enigmatic. Here we have dissected the unknown molecular steps of signaling-driven vRNP export. We identified RSK1 as downstream target of virus-activated ERK signaling. While RSK2 displays an antiviral role, we demonstrate for the first time a virus-supportive function of RSK1, migrating to the nucleus to phosphorylate NP, the major constituent of vRNPs. This drives association with viral M1 at the chromatin, important for vRNP export. Inhibition or knockdown of MEK, ERK or RSK1 caused impaired vRNP export actions of different RSK isoforms.
2020-06-18 | PXD016638 | Pride
Project description:Castration-resistant prostate cancer (CRPC) marks the advanced and lethal stage of prostate cancer (PCa). TRIM28, also known as KAP1, is a transcriptional regulator recently shown to promote CRPC cell proliferation and xenograft tumor growth. Nonetheless, knowledge gaps persist regarding the mechanisms underlying TRIM28 upregulation in CRPC as well as the genomic targets regulated by TRIM28. Here, we report that TRIM28 is a novel E2F1-target in CRPC. Using an integrated genomic approach, we have demonstrated that TRIM28 forms a positive feedback loop to promote the transcription activation and genomic function of E2F1 independent of Rb status. Furthermore, we identified RSK1 as a kinase that directly phosphorylates TRIM28 at S473, and as such, RSK1 drives the TRIM28-E2F1 feedback loop. Accordingly, pS473-TRIM28 promotes CRPC progression, which is mitigated by RSK inhibition. In summary, our study reveals a critical role of the RSK1–TRIM28–E2F1 axis in CRPC progression, which may be exploited as a vulnerability in treating Rb-deficient CRPC.
2025-06-17 | GSE287229 | GEO