Ligand bias underlies differential signaling of multiple FGFs via FGFR1
The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8,...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2024-04-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/88144 |
| _version_ | 1831877359342452736 |
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| author | Kelly Karl Nuala Del Piccolo Taylor Light Tanaya Roy Pooja Dudeja Vlad-Constantin Ursachi Bohumil Fafilek Pavel Krejci Kalina Hristova |
| author_facet | Kelly Karl Nuala Del Piccolo Taylor Light Tanaya Roy Pooja Dudeja Vlad-Constantin Ursachi Bohumil Fafilek Pavel Krejci Kalina Hristova |
| author_sort | Kelly Karl |
| collection | DOAJ |
| description | The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight. |
| first_indexed | 2024-04-24T13:58:54Z |
| format | Article |
| id | doaj.art-59cd46cf169246dd8f9d3ba3c0045635 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2025-03-21T21:14:46Z |
| publishDate | 2024-04-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj.art-59cd46cf169246dd8f9d3ba3c00456352024-05-29T08:20:50ZengeLife Sciences Publications LtdeLife2050-084X2024-04-011210.7554/eLife.88144Ligand bias underlies differential signaling of multiple FGFs via FGFR1Kelly Karl0Nuala Del Piccolo1https://orcid.org/0000-0002-5104-7322Taylor Light2Tanaya Roy3https://orcid.org/0000-0003-0939-7158Pooja Dudeja4Vlad-Constantin Ursachi5Bohumil Fafilek6https://orcid.org/0000-0002-3869-7937Pavel Krejci7https://orcid.org/0000-0003-0618-9134Kalina Hristova8https://orcid.org/0000-0003-4274-4406Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, United StatesDepartment of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, United StatesDepartment of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, United StatesDepartment of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, United StatesDepartment of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Institute of Animal Physiology and Genetics of the CAS, Brno, Czech RepublicDepartment of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech RepublicDepartment of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Institute of Animal Physiology and Genetics of the CAS, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech RepublicDepartment of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Institute of Animal Physiology and Genetics of the CAS, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech RepublicDepartment of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, United StatesThe differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.https://elifesciences.org/articles/88144signal transductionFGFRbiased signaling |
| spellingShingle | Kelly Karl Nuala Del Piccolo Taylor Light Tanaya Roy Pooja Dudeja Vlad-Constantin Ursachi Bohumil Fafilek Pavel Krejci Kalina Hristova Ligand bias underlies differential signaling of multiple FGFs via FGFR1 eLife signal transduction FGFR biased signaling |
| title | Ligand bias underlies differential signaling of multiple FGFs via FGFR1 |
| title_full | Ligand bias underlies differential signaling of multiple FGFs via FGFR1 |
| title_fullStr | Ligand bias underlies differential signaling of multiple FGFs via FGFR1 |
| title_full_unstemmed | Ligand bias underlies differential signaling of multiple FGFs via FGFR1 |
| title_short | Ligand bias underlies differential signaling of multiple FGFs via FGFR1 |
| title_sort | ligand bias underlies differential signaling of multiple fgfs via fgfr1 |
| topic | signal transduction FGFR biased signaling |
| url | https://elifesciences.org/articles/88144 |
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