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Receptor association and tyrosine phosphorylation of S6 kinases

På svenska

Author

  • H Rebholz
  • G Panasyuk
  • T Fenton
  • I Nemazanyy
  • T Valovka
  • M Flajolet
  • Lars Rönnstrand
  • L Stephens
  • A West
  • IT Gout

Summary, in English

Ribosomal protein S6 kinase (S6K) is activated by an array of mitogenic stimuli and is a key player in the regulation of cell growth. The activation process of S6 kinase involves a complex and sequential series of multiple Ser/Thr phosphorylations and is mainly mediated via phosphatidylinositol 3-kinase (PI3K)-3-phosphoinositide-dependent protein kinase-1 (PDK1) and mTor-dependent pathways. Upstream regulators of S6K, such as PDK1 and protein kinase B (PKB/Akt), are recruited to the membrane via their pleckstrin homology (PH) or protein-protein interaction domains. However, the mechanism of integration of S6K into a multi-enzyme complex around activated receptor tyrosine kinases is not clear. In the present study, we describe a specific interaction between S6K with receptor tyrosine Such as platelet-derived growth factor receptor (PDGFR). The kinases, interaction with PDGFR is mediated via the kinase or the kinase extension domain of S6K. Complex formation is inducible by growth factors and leads to S6K tyrosine phosphorylation. Using PDGFR mutants, we have shown that the phosphorylation is exerted via a PDGFR-src pathway. Furthermore, src kinase phosphorylates and coimmunoprecipitates with S6K in vivo. Inhibitors towards tyrosine kinases, such as genistein and PP1, or src-specific SU6656, but not PI3K and mTor inhibitors, lead to a reduction in tyrosine phosphorylation of S6K. In addition, we mapped the sites of tyrosine phosphorylation in S6K1 and S6K2 to Y39 and Y45, respectively. Mutational and immunofluorescent analysis indicated that phosphorylation of S6Ks at these sites does not affect their activity or subcellular localization. Our data indicate that S6 kinase is recruited into a complex with RTKs and src and becomes phosphorylated on tyrosine/s in response to PDGF or serum.

Publishing year

2006

Language

English

Pages

2023-2036

Publication/Series

The FEBS Journal

Volume

273

Issue

9

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Biochemistry and Molecular Biology

Keywords

  • src
  • kinases
  • receptor tyrosine
  • AGC kinases
  • platelet-derived growth factor receptor
  • ribosomal protein S6 kinase

Status

Published

ISBN/ISSN/Other

  • ISSN: 1742-464X