The p90 RSK Family Members: Common Functions and Isoform Specificity

Lara, Romain; Seckl, Michael J.; Pardo, Olivier E.

doi:10.1158/0008-5472.can-12-4448

Cited by 107 publications

(142 citation statements)

References 52 publications

Supporting

Mentioning

140

Contrasting

Order By: Relevance

“…in regulation of cellular division, survival, and differentiation via phosphorylation of numerous intracellular proteins ( (Romeo et al, 2012) and references therein). Four RSK genes (RSK1eRSK4) have been identified in mammals, and RSK orthologs have been described in D. melanogaster and Caenorhabditis elegans, but not in yeast and plants (Hauge and Fr€ odin, 2006;Lara et al, 2013).…”

Section: -Kda Rps6 Kinase (Rsk1ersk4)mentioning

confidence: 99%

Ribosomal Protein S6 Phosphorylation

Meyuhas¹

2015

International Review of Cell and Molecular Biology

245

202

View full text Add to dashboard Cite

Section: -Kda Rps6 Kinase (Rsk1ersk4)mentioning

confidence: 99%

Ribosomal Protein S6 Phosphorylation

Meyuhas¹

2015

International Review of Cell and Molecular Biology

245

202

View full text Add to dashboard Cite

“…The RSK family consists of four isoforms (RSK1-4) and is of particular interest in brain function because loss-of-function mutations in the RPS6KA3 gene (gene encoding RSK2) cause Coffin-Lowry syndrome, an intellectual disability characterized by psychomotor deficits, digit and facial dysmorphisms, progressive skeletal deformations, and severe cognitive impairment (24). ERK directly phosphorylates RSK at several residues, including Thr359/Ser363 (25). ERK1/2-dependent phosphorylation and activation of RSK at Thr359/Ser363 within its carboxyl-terminal domain enable autophosphorylation of RSK at Ser380, which is critical for maximal RSK activity (26).…”

Section: Erk But Not Mtor Signaling Is Elevated In the Cortex Of Fmr1 Komentioning

confidence: 99%

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Sawicka

Pyronneau

Chao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.F ragile X syndrome (FXS) is the most common heritable form of intellectual disability and a leading genetic cause of autism. Individuals with FXS typically suffer from a range of cognitive and behavioral deficits that can include anxiety, stereotypic movements, hyperactivity, seizures, and aggression, as well as social deficits typical of autism (1). FXS is caused by transcriptional silencing or mutation of the FMR1 gene encoding the RNA-binding protein, FMRP (fragile X mental retardation protein). FMRP binds to >1,000 mRNAs, including transcripts encoding both preand postsynaptic proteins important for synaptic function, and represses their translation via ribosome stalling (2). Loss of FMRP expression in fragile X syndrome would be expected to cause translational derepression of these target mRNAs.FMRP is strategically localized to dendrites, dendritic spines, axons, and cell bodies to control protein synthesis. Loss of FMRP causes enhanced protein synthesis, which can lead to altered spine morphology, synaptic circuits, and synaptic function with robust effects on higher cognitive function. The excessive, unchecked protein synthesis and impaired stimulus-induced protein synthesis are considered to be major contributors to the pathophysiology of fragile X (3-5). Increased protein synthesis has been demonstrated in whole-animal st...

show abstract

“…RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1)(2)(3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally.…”

Section: Introductionmentioning

confidence: 99%

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Deng

Jiang

et al. 2017

Oncology Letters

View full text Add to dashboard Cite

Abstract. Ribosomal S6 kinases (RSKs) are directly regulated by extracellular signal-regulated kinase (ERK) signaling and are implicated in cell growth, survival, motility and senescence. The present study observed that RSK1 was overexpressed in primary untreated leukemia patient bone marrow samples compared with the expression at the complete remission stage, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). In addition, a high RSK1 expression (relative expression ≥10) was associated with a significantly shorter overall survival (P=0.038) compared with that in patients with low RSK1 expression (relative expression <10). The current study also investigated the effect of luteolin, a novel p90 ribosomal S6 kinase (RSK) inhibitor extracted from Reseda odorata L., which shows strong biochemical functions including anti-allergy, anti-inflammation and anti-cancer functions, in MOLM-13 and Kasumi-1 leukemic cells. The cell viability, apoptosis and migration ability analysis were assessed by performing a cell counting kit-8 assay, Annexin V-FITC/PI double staining and migration filter assay, respectively. The results indicated that luteolin inhibited the growth of the leukemic cell lines through induction of apoptosis, while the migration ability was also suppressed. Overexpression of RSK1 by plasmid transfection was found to decrease the luteolin-induced apoptosis and migration capabilities. By contrast, knockdown of the RSK1 expression by small interfering RNA appeared to induce the same effect as luteolin on MOLM-13 and Kasumi-1 leukemic cells. In conclusion, these results suggest that luteolin inhibits leukemic cell proliferation and induces apoptosis by inhibition of the RSK1 pathways. IntroductionRibosomal S6 kinases (RSKs) are a family of serine/threonine protein kinases that are directly regulated by extracellular signal-regulated kinase (ERK) signaling. RSK1, a member of the RSK family, was initially identified as an X-linked gene in patients with mental retardation (1-3). Typically, RSK is expressed in the cerebellum during embryogenesis and silenced postnatally. Aberrant RSK signaling is integral for various types of cancer, including breast, colon and renal cancer, as well as melanoma. Li et al (4) observed that the p90 RSK2-cAMP response element-binding protein (CREB) pathway is commonly activated in diverse metastatic human cancer cells. Degen et al (5) also demonstrated this phenomenon, and further observed that overexpression of RSK3 and RSK1 supports cellular proliferation under the PI3K signaling pathway blockade. This occurs through the inhibition of apoptosis and regulation of cellular translation in squamous carcinoma cell through phosphorylation of RSK and eukaryotic translation initiation factor 4B. It is thus reported that RSK1 serves a role in squamous carcinoma cell growth and proliferation. In addition, Cohen et al (6) observed that RSK1 overexpression is associated with sunitinib resistance in renal cell carcinoma cell lines. Elf et al (7) also reported that, altho...

show abstract

The p90 RSK Family Members: Common Functions and Isoform Specificity

Cited by 107 publications

References 52 publications

Ribosomal Protein S6 Phosphorylation

Ribosomal Protein S6 Phosphorylation

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Luteolin, a novel p90 ribosomal S6 kinase inhibitor, suppresses proliferation and migration in leukemia cells

Contact Info

Product

Resources

About