title: RSK2 regulates endocytosis of FGF receptor 1 by phosphorylation on serine 789.
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.
authors.affiliation: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway [2] Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Nadratowska-Wesolowska
authors.affiliation: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway [2] Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: E M
authors.initials: EM
authors.lastname: Haugsten
authors.affiliation: Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Zakrzewska
authors.affiliation: Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Jakimowicz
authors.affiliation: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway [2] Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: Department of Protein Biotechnology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Pajdzik
authors.affiliation: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway [2] Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Wesche
authors.affiliation: 1] Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Montebello, Oslo, Norway [2] Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Wiedlocha
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004705:Endocytosis; D005346:Fibroblast Growth Factors / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D012694:Serine / Q000378:metabolism
chemical_list: D012694:Serine; D005346:Fibroblast Growth Factors; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3