The RSK family of kinases: Emerging roles in cellular signalling
ABSTRACT The 90 kDa ribosomal S6 kinase (RSK) family of proteins is a group of highly conserved Ser/Thr kinases that regulate diverse cellular processes, such as cell growth, cell motility, cell survival and cell proliferation. RSKs are downstream effectors of the Ras-extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling cascade. Significant advances in the field of RSK and ERK/MAPK signalling have occurred in the past few years, including biological insights and the discovery of novel substrates and new RSK regulatory mechanisms. Collectively, these data expand the current models of RSK signalling and highlight potential directions of research in RSK-mediated survival, growth, proliferation and migration.
- SourceAvailable from: Jianmin Zhang
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- "result in the subsequent pro-survival signaling cascade, which is the activation of the 90 kDa ribosomal S6 kinase and its downstream pathway . The transcriptional factor cAMP-response element binding protein (CREB) phosphorylation is ribosomal S6 kinase-mediated and facilitates the neuron survival through increased transcription of pro-survival genes, such as Bcl2 family members (Anjum and Blenis, 2008). Indeed, the expression of Bcl-2 was reduced when TrkB was knocked down in this study (Fig. 1). "
ABSTRACT: N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), an N-acetyl serotonin's derivative, selectively activates tropomyosin-related kinase receptor B (TrkB). This study is to investigate a potential role of HIOC on ameliorating early brain injury after experimental subarachnoid hemorrhage (SAH). One hundred and fifty-six adult male Sprague-Dawley rats were used. SAH model was induced by endovascular perforation. TrkB small interfering RNA (siRNA) or scramble siRNA was injected intracerebroventricularly 24hours before SAH. HIOC was administrated intracerebroventricularly 3hours after SAH and compared with brain-derived neurotrophic factor (BDNF). SAH grade and neurologic scores were evaluated for the outcome study. For the mechanism study, the expression of TrkB, phosphorylated TrkB (p-TrkB), phosphorylated extracellular signal regulated kinase (p-ERK), B-cell lymphoma 2 (Bcl-2) and cleaved caspase 3 (CC3) were detected by Western blots, and neuronal injury was determined by double immunofluorescence staining of neuronal nuclei and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labeling. Knocking down of TrkB decreased the expression of Bcl-2 and aggravated neurologic deficits 24hours after SAH. HIOC activated TrkB/ERK pathway, decreased neuronal cell death, improved neurobehavioral outcome, and these effects were abolished by TrkB siRNA. HIOC was more potent than BDNF in reduction of apoptosis 24hours post-SAH. Thus, we conclude that administration of HIOC activated TrkB/ERK signaling cascade and attenuated early brain injury after SAH. HIOC may be a promising agent for further treatment for SAH and other stroke events. Copyright © 2015. Published by Elsevier Inc.Neurobiology of Disease 04/2015; 78. DOI:10.1016/j.nbd.2015.01.009 · 5.20 Impact Factor
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- "RSK2 acts as a protection against TNF-a-mediated inhibition of bone formation. RSK2 is a growth-factor-regulated kinase that was reported to mediate cell cycle progression and cell proliferation in numerous cell types and organisms (Anjum and Blenis, 2008; Cho et al., 2005; David et al., 2005; Eisinger-Mathason et al., 2008; Lin et al., 2008; Romeo and Roux, 2011; Wang et al., 2010). We now report the reduced in vitro growth ability of osteoblast lacking RSK2. "
ABSTRACT: Objective Arthritis is a chronic inflammatory disease characterised by immune cell infiltration and mesenchymal cell expansion in the joints. Although the role of immune cells in arthritis is well characterised, the development of mesenchymal cell hyperplasia needs to be better defined. Here, we analysed the role of the ribosomal S6 kinase Rsk2, which we found to be highly activated in joints of patients with arthritis, in the development of mesenchymal cell hyperplasia. Methods We genetically inactivated Rsk2 in the tumour necrosis factor (TNF)-α transgenic (TNFtg) mice, an animal model for human inflammatory arthritis. Clinical and histological signs of arthritis as well as molecular markers of inflammation and joint destruction were quantified. Fibroblast-like synoviocytes (FLS) were characterised in vitro and the effect of Rsk2 deletion on the pattern of gene expression was determined. Results Rsk2 deficiency in TNFtg mice results in earlier and exacerbated inflammation as well as increased bone and cartilage destruction. The production of inflammatory cytokines, matrix metalloproteinases and osteoclastogenic molecules was significantly increased in vivo upon Rsk2 inactivation. Bone marrow deficient in Rsk2 could not transfer this phenotype, indicating that Rsk2 expression in mesenchymal cells controls the course of arthritis. Indeed, Rsk2 deficiency was associated with a more activated phenotype and higher proliferative capacity of FLS, thereby increasing cytokines and production of matrix proteinases. Conclusions Rsk2 emerges as a key regulator of mesenchymal cell numbers in the joint and thereby could be targeted to control the inflammatory and tissue-destructive feature of joints in arthritis.Annals of the Rheumatic Diseases 11/2014; DOI:10.1136/annrheumdis-2014-205618 · 10.38 Impact Factor
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- "Subsequently, activated CTKD phosphorylates Ser380 in the linker region, which recruits PDK1. This is followed by phosphorylation of Ser221 in NTKD by PDK1, which allows RSKs to regulate function of its substrates  . "
ABSTRACT: The members of p90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases are downstream effectors of MAPK/ERK pathway that regulate diverse cellular processes including cell growth, proliferation and survival. In carcinogenesis, RSKs are thought to modulate cell motility, invasion and metastasis. Herein, we have studied an involvement of RSKs in FGF2/FGFR2-driven behaviours of mammary epithelial and breast cancer cells. We found that both silencing and inhibiting of FGFR2 attenuated phosphorylation of RSKs, whereas FGFR2 overexpression and/or its stimulation with FGF2 enhanced RSKs activity. Moreover, treatment with ERK, Src and p38 inhibitors revealed that p38 kinase acts as an upstream RSK2 regulator. We demonstrate for the first time that in FGF2/FGFR2 signalling, p38 but not MEK/ERK, indirectly activated RSK2 at Tyr529, which facilitated phosphorylation of its other residues (Thr359/Ser363, Thr573 and Ser380). In contrast to FGF2-triggered signalling, inhibition of p38 in the EGF pathway affected only RSK2-Tyr529, without any impact on the remaining RSK phosphorylation sites. p38-mediated phosphorylation of RSK2-Tyr529 was crucial for transactivation of residues located at kinase C-terminal domain and linker-region, specifically, in the FGF2/FGFR2 signalling pathway. Furthermore, we show that FGF2 promoted anchorage-independent cell proliferation, formation of focal adhesions and cell migration, which was effectively abolished by treatment with RSKs inhibitor (FMK). These indicate that RSK2 activity is indispensable for FGF2/FGFR2-mediated cellular effects. Our findings identified a new FGF2/FGFR2-p38-RSK2 pathway which may play a significant role in the pathogenesis and progression of breast cancer, and hence, may present a novel therapeutic target in the treatment of FGFR2-expressing tumours.Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 07/2014; 1843(11). DOI:10.1016/j.bbamcr.2014.06.022 · 5.30 Impact Factor