Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

Chiara Francavilla, KristofferT G. Rigbolt, KristinaB Emdal, Gianni Carraro, Erik Vernet, DorteB Bekker-Jensen, Werner Streicher, Mats Wikström, Michael Sundström, Saverio Bellusci, Ugo Cavallaro, Blagoy Blagoev, JesperV Olsen

Research output: Contribution to journalArticlepeer-review

Abstract

The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation, whereas FGF-10 promotes receptor recycling and cell migration. By combining mass-spectrometry-based quantitative proteomics with fluorescence microscopy and biochemical methods, we find that FGF-10 specifically induces the rapid phosphorylation of tyrosine (Y) 734 on FGFR2b, which leads to PI3K and SH3BP4 recruitment. This complex is crucial for FGFR2b recycling and responses, given that FGF-10 stimulation of either FGFR2b_Y734F mutant- or SH3BP4-depleted cells switches the receptor endocytic route to degradation, resulting in decreased breast cancer cell migration and the inhibition of epithelial branching in mouse lung explants. Altogether, these results identify an intriguing ligand-dependent mechanism for the control of receptor fate and cellular outputs that may explain the pathogenic role of deregulated FGFR2b, thus offering therapeutic opportunities.

Original languageEnglish
Pages (from-to)707-722
Number of pages16
JournalMolecular Cell
Volume51
Issue number6
DOIs
Publication statusPublished - Sep 26 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs'. Together they form a unique fingerprint.

Cite this