title: Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs.
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.
authors.affiliation: Department of Proteomics, NNF Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Chiara
authors.initials: C
authors.lastname: Francavilla
authors.forename: Kristoffer T G
authors.initials: KT
authors.lastname: Rigbolt
authors.forename: Kristina B
authors.initials: KB
authors.lastname: Emdal
authors.forename: Gianni
authors.initials: G
authors.lastname: Carraro
authors.forename: Erik
authors.initials: E
authors.lastname: Vernet
authors.forename: Dorte B
authors.initials: DB
authors.lastname: Bekker-Jensen
authors.forename: Werner
authors.initials: W
authors.lastname: Streicher
authors.forename: Mats
authors.initials: M
authors.lastname: Wikström
authors.forename: Michael
authors.initials: M
authors.lastname: Sundström
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
authors.forename: Blagoy
authors.initials: B
authors.lastname: Blagoev
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
mesh_terms: D000818:Animals; D002465:Cell Movement; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism*; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis; D040901:Proteomics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: C496464:Fgf10 protein, mouse; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D008024:Ligands; D051523:Fibroblast Growth Factor 7; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2