Wang Mong-Lien, Panasyuk Ganna, Gwalter Jodie, Nemazanyy Ivan, Fenton Tim, Filonenko Valeriy, Gout Ivan
Department of Structural and Molecular Biology, University College London, Gower Street, Darwin Building, London WC1E 6BT, United Kingdom.
Biochem Biophys Res Commun. 2008 May 2;369(2):382-7. doi: 10.1016/j.bbrc.2008.02.032. Epub 2008 Feb 15.
Ribosomal protein S6 kinase (S6K) is a key player in the regulation of cell growth and energy metabolism via the mTOR and PI3K signalling pathways. The activity and subcellular localization of S6K are regulated by multiple S/T phosphorylations in response to diverse extracellular stimuli. Downregulation of S6K signalling occurs through the action of S/T phosphatases (PP2A and PP1) and tumor suppressors (TSC1/2 and PTEN). We report here that, in addition to phosphorylation, S6Ks are ubiquitinated in cells. The pattern of ubiquitination and the effect of proteasomal inhibitors on the steady-state level of transiently overexpressed and endogenous S6Ks point to proteasome-mediated degradation of ubiquitinated S6Ks. Furthermore, we found that the site(s) of ubiquitination are located in the kinase domain and that the N- and C-terminal regulatory regions modulate the efficiency of S6K ubiquitination. This study suggests that S6K signalling also could be regulated through the proteasome-mediated turnover of S6Ks.
核糖体蛋白S6激酶（S6K）是通过mTOR和PI3K信号通路调控细胞生长和能量代谢的关键因子。S6K的活性和亚细胞定位受多种S/T磷酸化调节，以响应不同的细胞外刺激。S6K信号通路的下调通过S/T磷酸酶（PP2A和PP1）和肿瘤抑制因子（TSC1/2和PTEN）的作用实现。我们在此报告，除了磷酸化外，S6K在细胞中还会发生泛素化。泛素化模式以及蛋白酶体抑制剂对瞬时过表达和内源性S6K稳态水平的影响表明，蛋白酶体介导了泛素化S6K的降解。此外，我们发现泛素化位点位于激酶结构域，并且N端和C端调节区域调节S6K泛素化的效率。这项研究表明，S6K信号通路也可能通过蛋白酶体介导的S6K周转来调节。
