Identification and characterization of novel RSK substrates

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The Ras-dependent extracellular signal-regulated kinase (ERK) cascade responds to a wide array of extracellular stimuli to regulate diverse biological functions, including cell proliferation, differentiation, migration and survival. This pathway plays particularly important roles during embryogenesis, where ERK signalling regulates various developmental processes downstream of growth factors, including gastrulation, neural patterning, limb development and placentation. Proper regulation of this signalling pathway is thus crucial during embryogenesis and adulthood, as activating/inactivating mutations within this cascade lead to various developmental disorders and diseases. Downstream of the Ras/ERK signalling cascade lies the p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases (RSK1-4). These enzymes are thought to be multifunctional ERK effectors involved in cell growth and proliferation, but relatively little is known regarding their specific targets and mechanisms of action. Through the years, our lab has developed mouse models to specifically address the role of the RSK isoforms downstream of the Ras/ERK pathway. In this proposal, we intend to use a quantitative proteomics method to identify novel phosphorylation substrates of the RSK isoforms. This approach has already resulted in the identification of a novel RSK substrate, which we intend to study in detail and determine the role of RSK in its regulation. This project provides a great opportunity to train graduate students for research in the biological sciences, including cell biology, mouse genetics, molecular biology, biochemistry, microscopy and proteomics. In the long-term, the technology that we are developing will be useful to address other aspects of RSK signalling and these results will be the basis of our research for years to come.