Article

The RSK family of kinases: Emerging roles in cellular signalling

Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 11/2008; 9(10):747-58. DOI: 10.1038/nrm2509
Source: PubMed

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.

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    • "Other influenced kinase, WNK1 was reported to be required for EGF-dependent stimulation of ERK5 without affecting the activation of ERK1/2, JNK or p38 MAP kinases[36]. Upregulated RSK family of proteins also play an important role in many biological functions, ranging from the regulation of transcription, translation and protein stability to the control of cell survival , cell motility, cell growth and proliferation[37]. We suggest that MSC in the tumor microenvironment respond to the stress mediated by chemotherapy by the secretion of cytokines and chemokines reminiscent of a senescence-associated secretory phenotype (SASP). "
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    ABSTRACT: Cells of the tumor microenvironment are recognized as important determinants of the tumor biology. The adjacent non-malignant cells can regulate drug responses of the cancer cells by secreted paracrine factors and direct interactions with tumor cells. Human mesenchymal stromal cells (MSC) actively contribute to tumor microenvironment. Here we focused on their response to chemotherapy as during the treatment these cells become affected. We have shown that the secretory phenotype and behavior of mesenchymal stromal cells influenced by cisplatin differs from the naïve MSC. MSC were more resistant to the concentrations of cisplatin, which was cytotoxic for tumor cells. They did not undergo apoptosis, but a part of MSC population underwent senescence. However, MSC pretreatment with cisplatin led to changes in phosphorylation profiles of many kinases and also increased secretion of IL-6 and IL-8 cytokines. These changes in cytokine and phosphorylation profile of MSC led to increased chemoresistance and stemness of breast cancer cells. Taken together here we suggest that the exposure of the chemoresistant cells in the tumor microenvironment leads to substantial alterations and might lead to promotion of acquired microenvironment-mediated chemoresistance and stemness.
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    • "RSK also phosphorylates the subunit of mTORC1, Raptor (Carriere et al., 2008), and S6 (Roux et al., 2007), as well as eEF2k (Bain et al., 2007). Indeed, both RAF and PI3K pathways stimulate mTORC1 signaling (Anjum and Blenis, 2008; Pearce et al., 2010). Activation of PI3K occurs by a broad array of different stimuli in a variety of different cell types. "
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    • "Thr421/Ser424 with increasing age in the biceps brachii. This finding suggests that the phosphorylation of Akt and MAPK activates mTOR in order to increase the proliferation of muscle satellite cells (Rahnert et al., 2011; Bodine et al., 2001, Anjum and Blenis, 2008). Previous publications have suggested the existence of the ROS-induced activation of MAPK pathways and age-dependent changes in the activation status of MAPK in various tissues, including brain, lung, muscle , and liver (Son et al., 2011). "
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    ABSTRACT: Aging is characterized by a progressive decrease of cellular functions, because cells gradually lose their capacity to respond to injury. Increased oxidative stress is considered to be one of the major contributors to age-related changes in all organs including the liver. Our study has focused on elucidating whether important antioxidative enzymes, the mTOR pathway, and MAPKs exhibit age-dependent changes in the liver of rats during aging. We found an age-dependent increase of GSH in the cytosol and mitochondria. The aged liver showed an increased SOD enzyme activity, while the CAT enzyme activity decreased. HO-1 and NOS-2 gene expression was lower in adult rats, but up-regulated in aged rats. Western blot analysis revealed that SOD1, SOD2, GPx, GR, γ-GCL, and GSS were age-dependent up-regulated, while CAT remained constant. We also demonstrated that the phosphorylation of Akt, JNK, p38, and TSC2Ser1254 decreased while ERK1/2 and TSC2Thr1462 increased agedependently. Furthermore, our data show that the mTOR pathway seems to be activated in livers of aged rats, and hence stimulating cell proliferation/regeneration, as confirmed by an age-dependent increase of PCNA and p-eIF4ESer209 protein expression. Our data may help to explain the fact that liver cells only proliferate in cases of necessity, like injury and damage. In summary, we have demonstrated that, age-dependent changes of the antioxidant system and stress-related signaling pathways occur in the livers of rats, which may help to better understand organ aging. © 2015, Leibniz Research Centre for Working Environment and Human Factors. All rights reserved.
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