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Protein Kinase C Phosphorylates Ribosomal Protein S6 Kinase ßII and Regulates Its Subcellular Localization

Ludwig Institute for Cancer Research, London W1W 7BS,¹ Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, London WC1E 6BT,² Division of Molecular Physiology, School of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee DD1 5EH,⁵ Cancer Research United Kingdom, London WC2A 3PX, United Kingdom,⁶ Department of Structure and Function of Nucleic Acid, The Institute of Molecular Biology and Genetics, Kyiv 143,³ L'viv State Medical University, L'viv 290010, Ukraine⁴

Received 5 July 2002/ Returned for modification 10 September 2002/ Accepted 29 October 2002

The ribosomal protein S6 kinase (S6K) belongs to the AGC family of Ser/Thr kinases and is known to be involved in the regulation of protein synthesis and the G₁/S transition of the cell cycle. There are two forms of S6K, termed S6K and S6Kß, which have cytoplasmic and nuclear splice variants. Nucleocytoplasmic shuttling has been recently proposed for S6K, based on the use of the nuclear export inhibitor, leptomycin B. However, the molecular mechanisms regulating subcellular localization of S6Ks in response to mitogenic stimuli remain to be elucidated. Here we present data on the in vitro and in vivo phosphorylation of S6Kß, but not S6K, by protein kinase C (PKC). The site of phosphorylation was identified as S486, which is located within the C-terminal nuclear localization signal. Mutational analysis and the use of phosphospecific antibodies provided evidence that PKC-mediated phosphorylation at S486 does not affect S6K activity but eliminates the function of its nuclear localization signal and causes retention of an activated form of the kinase in the cytoplasm. Taken together, this study uncovers a novel mechanism for the regulation of nucleocytoplasmic shuttling of S6KßII by PKC-mediated phosphorylation.

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