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The role of the S6K2 splice isoform in mTOR/S6K signalling and cellular functions

Myronova, O; (2016) The role of the S6K2 splice isoform in mTOR/S6K signalling and cellular functions. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Ribosomal S6 kinase (S6K) is a member of the AGC family of serine/threonine protein kinases and plays a key role in diverse cellular processes, including cell growth, survival and metabolism. Activation of S6K by growth factors, amino acids, energy levels and hypoxia is mediated by the mTOR and PI3K signalling pathways. Dysregulation of S6K activity has been implicated in a number of human pathologies, including cancer, diabetes, obesity and ageing. The family of S6Ks consists of two proteins S6K1 and S6K2, which are encoded by different genes. Most of research has been done on S6K1, while little is currently known about specific functions of S6K2. Recently, several novel splicing variants of human S6K2, termed S6K2-S1, S6K2-S2 and S6K2-S3, have been identified in our laboratory. The aim of this thesis was therefore to study the function of S6K2-S1 splicing isoform in normal and cancer cells and its role in the regulation of mTORC1/S6K signalling. Initially, detailed bioinformatic analysis of human and mouse databases in combination with an alternative splicing potential of S6K2 gene revealed three novel splicing isoforms. S6K2-S1 splicing isoform is the product of exon 9 alternative splicing, which results in the formation of a truncated splice variant, lacking the kinase domain. We found that S6K2-S1 has the potential to integrate into the mTORC1 signalling complex via specific interaction with the substrate-presenting protein Raptor. Functional analysis of S6K2-S1 revealed that it could inhibit some of mTOR functions in starved conditions and mediate pro-apoptotic signalling. Furthermore, stable overexpression of S6K2-S1 protein in different cell lines inhibited cell migration and dramatically reduced anchorage-independent colony growth in soft agar. Importantly, S6K2-S1 splice variant reduced A549 cell in vivo tumour growth in nude mice, while full length S6K2 promoted in vivo tumour formation. Together, the data from this thesis revealed the existence of novel S6K2 splicing isoforms and uncovered a dominant-negative effect of S6K2-S1 on mTORC1 signalling and its tumour suppressive function in cell-based models and xenograft studies.

Type: Thesis (Doctoral)
Title: The role of the S6K2 splice isoform in mTOR/S6K signalling and cellular functions
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/1493002
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