A molecular switch underlying FGF receptor responses

Fibroblast Growth Factors (FGFs) control key cellular processes during early organ development and in adult life by activating members of the FGF receptor (FGFR) family. Deregulated FGFR signaling and trafficking have been associated to skeletal disorders and cancer, pointing to the need of a better understanding of FGFR regulation and signaling specificity. This study elucidates a long lasting conundrum of how stimulation of FGFR2b with different ligands (FGF-7 and FGF-10) generates two fundamentally distinct biological outputs.

Professor Olsen´s research team in the Department of Proteomics, in collaboration with the Protein Function and Interaction Group at CPR and international partners, made use of functional proteomics (a combination of MS-based quantitative proteomics and functional assays) to identify a ligand-dependent mechanism for the control of FGFR fate and cellular outputs. Using high-resolution Orbitrap mass spectrometry, almost 1000 tyrosine-phosphorylated sites have been quantified in a time-resolved manner to comprehensively dissect FGF-7 and FGF-10 dynamic signaling. The dynamically regulated tyrosine phosphoproteome revealed that FGF-7 mainly targets proteins involved in cell proliferation whereas FGF-10 induces phosphorylation of proteins involved in trafficking and cell migration. Surprisingly, FGF-10 specifically induced Y734 phosphorylation on FGFR2b resulting in the early recruitment of PI3K and SH3BP4. The FGFR2b-PI3K-SH3BP4 complex is required not only for switching the receptor sorting from the degradation to the recycling route, but more importantly, for cell migration and epithelial lung branching.

This study demonstrates that FGF receptor trafficking dictates cellular fate and suggests that a prompt intervention of the spatio-temporal control of proximal RTK signaling could lead to more efficient and personalized therapies in medicine.

Title: Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs.

Authors: Chiara Francavilla, Kristoffer T.G. Rigbolt, Kristina B. Emdal, Gianni Carraro, Erik Vernet, Dorte B. Bekker-Jensen, Werner Streicher, Mats Wikström, Michael Sundström, Saverio Bellusci, Ugo Cavallaro, Blagoy Blagoev, Jesper V. Olsen.

Link to article in Molecular Cell