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.

journal_name

Oncogene

journal_title

Oncogene

authors

Nadratowska-Wesolowska B,Haugsten EM,Zakrzewska M,Jakimowicz P,Zhen Y,Pajdzik D,Wesche J,Wiedlocha A

doi

10.1038/onc.2013.425

subject

Has Abstract

pub_date

2014-10-02 00:00:00

pages

4823-36

issue

40

eissn

0950-9232

issn

1476-5594

pii

onc2013425

journal_volume

33

pub_type

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