Research

The p90 ribosomal S6 kinase familyuntitled

p90 ribosomal S6 kinases (RSKs) is a group of highly conserved Ser/Thr kinases that promotes cell proliferation, growth, motility and survival. In humans four different isoforms (RSK1, RSK2, RSK3, and RSK4) have been identified, with a shared sequence similarity of 73 – 80 %. RSKs are monomeric proteins composed by two kinase domains: a C-terminal kinase domain (CTKD) and an N-terminal kinase domain (NTKD) connected by a linker region. The two kinase domains did not develop by gene duplication but by gene fusion: the NTKD belongs to the protein kinase AGC family, whereas the CTKD belongs to the Ca2+/calmodulin-dependant protein kinase family (CAMKII family). RSKs loss of regulation has been linked to cancer, but our understanding of RSK function in disease progression is incomplete and is complicated by the fact that RSK isoforms play different roles in different cancer types.

Human p70 ribosomal S6 kinase 2

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p70 ribosomal protein S6 kinases (S6Ks) are activated by several different stimuli and have been shown to have important roles in protein synthesis regulation, mRNA splicing, cytoskeleton organization, cell proliferation and cell survival. In humans the S6K protein family has two members, S6K1 and S6K2. Due to the level of similarity, S6K1 has been considered the prototypical S6Ks and S6K2 has been largely neglected. However an increasing number of studies have indicated that S6K1 and S6K2 function differently. Recent data have shown that FGF-2 activate a signaling cascade that involves B-Raf, PKCε, S6K2 (but not S6K1) and hnRNPA1. B-Raf and PKCε activate S6K2 that in turn phosphorylates hnRNPA1. hnRNPA1 specifically recognises Bcl-xL and XIAP mRNAs and promotes their translation, leading to downregulation of apoptosis and promotion of cell survival. Our aim is to provide a detailed mechanistic and structural characterisation of S6K2-hnRNPA1 induction of drug resistance in Small Cell Lung Cancer.

Fragment Screening – XChem.

Arabidopsis thaliana p70 ribosomal S6 kinase 2

UntitledIn plants, like in most eukaryotes, the p70 ribosomal S6 kinases (S6Ks) pathway coordinates cell growth, cell proliferation, and stress response via modulating protein synthesis and ribosomal biogenesis. Studies in Arabidopsis thaliana (Arabidopsis) have shown that, similarly to in humans, the S6K family is composed of two members, called AtS6K1 and AtS6K2. Initial evidences suggest that AtS6K2 regulates responses to stresses and developmental cues. In fact, AtS6K2 is up regulated in response to cold and high-salinity stress and is co-expressed with genes involved in stress responsive regulation of plant growth. Furthermore, AtS6K2 plays an important role in chromosome stability and functions as a repressor of cell proliferation. In the context of future climate change predictions, we aim to understand how S6K2 modulates cellular responses to changes in the external environment in the model plant Arabidopsis. As such, our aim is to define how AtS6K2 allows plant cells to adapt to different environmental conditions. Plants are ideal to characterise S6K2 specific pathways, since our studies suggest that plant S6Ks represents the prototypical ribosomal kinase family. Plants have a much-reduced complexity since they do not have RSKs. In fact, humans have two homologues ribosomal protein kinase families: the p70 ribosomal S6 kinases (composed of two members, S6K1-2) and the p90 ribosomal S6 kinases (composed of four members, RSK1-4). 

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