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Elucidation of signaling pathways regulating ribosomal protein S6 kinases

Valovka, Taras; (2003) Elucidation of signaling pathways regulating ribosomal protein S6 kinases. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The ribosomal protein S6 kinase belongs to the AGC family of Ser/Thr kinases and is known to be involved in the regulation of translation and Gl/S transition of the cell cycle. In addition to playing an essential role in regulating cell growth, S6K appears to be a multifunctional protein, involved in the control of other cellular processes such as transcription, RNA processing, and apoptosis. Two human S6K forms have been identified, termed S6Kα and S6Kβ which have cytoplasmic and nuclear splicing variants. Both kinases have very high level of homology in kinase domain, but differ significantly in the N- and C-terminal regulatory regions. These differences and some variations in the pattern of phosphorylation sites may predestine the involvement of both kinases in distinct signaling events and cellular responses. This manuscript presents analysis of regulatory and functional properties of ribosomal S6Kα and its recently identified homologue S6Kβ. Recombinant full-length versions and a panel of deleted and point mutants of S6Kα and S6Kβ were created and used to study the mechanisms of mitogen-induced activation of these kinases. Furthermore, employment of specific inhibitors of mTOR/FRAP, PI-3'-K, PKC and MEK allowed us to study the contribution of these signaling molecules in the activation of S6Kα and S6Kβ by various mitogenic stimuli. Here we also present a detailed analysis of subcellular localisation of S6Kα and S6Kβ isoforms. Using confocal microscopy and a panel of mutants, we have described for the first time mitogen-regulated nucleocytoplasmic shuttling of S6KβII and addressed a critical role of PKC signaling in this process. A novel PKC phosphorylation site, specific for S6Kβ, was identified by mass spectrometry and found to be involved in the regulation of its subcellular distribution. Finally, we have developed tetracycline-inducible stable cell lines, overexpressing activated versions of four different isoforms of S6K. This model system allowed us to initiate studies on the role of individual S6K isoforms in the regulation of gene expression. In conclusion, this study demonstrates the existence of distinct signaling mechanisms, involved in the regulation of S6Kα and S6Kβ.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Elucidation of signaling pathways regulating ribosomal protein S6 kinases
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Biological sciences; Ribosomal proteins
URI: https://discovery.ucl.ac.uk/id/eprint/10102509
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