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RSK2 regulates endocytosis of FGF receptor 1 by phosphorylation on serine 789

Oncogene volume 33, pages 4823–4836 (2014)Cite this article

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Abstract

FGFR1 (fibroblast growth factor receptor 1) regulates many key cellular responses including proliferation, migration and differentiation through activation of signaling pathways. Irregularities in FGFR1 signaling have been implicated in several pathological conditions, including human cancer. In order to discover novel regulators of FGFR1 signaling, we performed yeast two-hybrid screens and identified RSK2 (p90 ribosomal S6 kinase 2) as a potential FGFR1 interaction partner. RSK2 belongs to the family of serine/threonine kinases that are activated through the Ras-MAPK signal transduction pathway. Both in vitro and in vivo experiments confirmed the interaction and we show that phosphorylated RSK2 binds to and phosphorylates serine 789 in the C-terminal tail of FGFR1. Inhibition of RSK2 activity led to prolonged tyrosine transphosphorylation of FGFR1. Furthermore, prevention of FGFR1 phosphorylation by inhibition of RSK2 activity or mutation of serine 789 to alanine reduced FGFR1 endocytosis and ubiquitination explaining mechanistically the prolonged signaling activity. We propose a novel regulatory mechanism whereby activated RSK2 directly interacts with and phosphorylates FGFR1, thereby modulating receptor signaling through regulation of endocytosis.

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Acknowledgements

This work was supported by grant PNRF-87-AI-1/07 from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund and by the Polish Ministry of Science and Higher Education (grant 0627/IP1/2011/71). The skilful technical assistance of Anne Gro Bergersen and Anne-Mari G. Pedersen is gratefully acknowledged. JW holds a senior scientist grant from South-Eastern Norway Regional Health Authority.

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Authors and Affiliations

  1. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway

    B Nadratowska-Wesolowska, E M Haugsten, Y Zhen, J Wesche & A Wiedlocha

  2. Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway

    B Nadratowska-Wesolowska, E M Haugsten, Y Zhen, J Wesche & A Wiedlocha

  3. Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland

    M Zakrzewska

  4. Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland

    P Jakimowicz & D Pajdzik

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  1. B Nadratowska-Wesolowska
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Correspondence to A Wiedlocha.

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Nadratowska-Wesolowska, B., Haugsten, E., Zakrzewska, M. et al. RSK2 regulates endocytosis of FGF receptor 1 by phosphorylation on serine 789. Oncogene 33, 4823–4836 (2014). https://doi.org/10.1038/onc.2013.425

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