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

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

doi:10.1016/j.molcel.2013.08.002

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

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

82 Citations (Scopus)

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 language	English
Journal	Molecular Cell
Volume	51
Issue number	6
Pages (from-to)	707-22
Number of pages	16
ISSN	1097-2765
DOIs	https://doi.org/10.1016/j.molcel.2013.08.002
Publication status	Published - 26 Sept 2013

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Francavilla, C., Rigbolt, K. T. G., Emdal, K. B., Carraro, G., Vernet, E., Bekker-Jensen, D. B., Streicher, W., Wikström, M., Sundström, M., Bellusci, S., Cavallaro, U., Blagoev, B., & Olsen, J. V. (2013). Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs. Molecular Cell, 51(6), 707-22. https://doi.org/10.1016/j.molcel.2013.08.002

Francavilla, C, Rigbolt, KTG, Emdal, KB, Carraro, G, Vernet, E, Bekker-Jensen, DB, Streicher, W, Wikström, M, Sundström, M, Bellusci, S, Cavallaro, U, Blagoev, B & Olsen, JV 2013, 'Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs', Molecular Cell, vol. 51, no. 6, pp. 707-22. https://doi.org/10.1016/j.molcel.2013.08.002

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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.",

author = "Chiara Francavilla and Rigbolt, {Kristoffer T.G.} and Emdal, {Kristina B} and Gianni Carraro and Erik Vernet and Bekker-Jensen, {Dorte B} and Werner Streicher and Mats Wikstr{\"o}m and Michael Sundstr{\"o}m and Saverio Bellusci and Ugo Cavallaro and Blagoy Blagoev and Olsen, {Jesper V}",

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T1 - Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

AU - Francavilla, Chiara

AU - Rigbolt, Kristoffer T.G.

AU - Emdal, Kristina B

AU - Carraro, Gianni

AU - Vernet, Erik

AU - Bekker-Jensen, Dorte B

AU - Streicher, Werner

AU - Wikström, Mats

AU - Sundström, Michael

AU - Bellusci, Saverio

AU - Cavallaro, Ugo

AU - Blagoev, Blagoy

AU - Olsen, Jesper V

PY - 2013/9/26

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N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2013.08.002

DO - 10.1016/j.molcel.2013.08.002

M3 - Journal article

C2 - 24011590

SN - 1097-2765

VL - 51

SP - 707

EP - 722

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

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

Abstract

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