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Increased thermal stability of FGF10 leads to ectopic signaling during development
AA. Czyrek, K. Baran, E. Hruba, A. Horackova, V. Bosakova, J. Chudzian, B. Fafilek, V. Laskova, V. Stepankova, D. Bednar, K. Karl, P. Kasparek, M. Bosakova, M. Killinger, T. Szotkowska, J. Prochazka, JT. Zieba, G. Rico-Llanos, J. Fric, S. Hadzic,...
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
NLK
Directory of Open Access Journals
od 2024
PubMed Central
od 1997
ProQuest Central
od 2024-01-01 do Před 1 rokem
Medline Complete (EBSCOhost)
od 2000-01-01
Health & Medicine (ProQuest)
od 2024-01-01 do Před 1 rokem
Springer Journals Complete - Open Access
od 2024-12-01
Springer Nature OA/Free Journals
od 2024-12-01
- MeSH
- fibroblastový růstový faktor 10 * metabolismus genetika chemie MeSH
- lidé MeSH
- myši MeSH
- plíce metabolismus embryologie MeSH
- receptory fibroblastových růstových faktorů metabolismus MeSH
- signální transdukce * MeSH
- stabilita proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.
Department of Biology Faculty of Medicine Masaryk University Brno 62500 Czech Republic
Department of Biophysics Faculty of Biotechnology University of Wroclaw Wroclaw 50 383 Poland
Department of Experimental Biology Faculty of Science Masaryk University Brno 62500 Czech Republic
Enantis Ltd Brno 62500 Czech Republic
Excellence Cluster Cardio Pulmonary Institute Justus Liebig University 35392 Giessen Germany
Institute of Animal Physiology and Genetics Czech Academy of Sciences Brno 60200 Czech Republic
Institute of Hematology and Blood Transfusion Prague 12800 Czech Republic
International Clinical Research Center St Anne's University Hospital Brno 65691 Czech Republic
Citace poskytuje Crossref.org
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- $a Czyrek, Aleksandra A $u Department of Biology, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic $u International Clinical Research Center, St. Anne's University Hospital, Brno, 65691, Czech Republic $u Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, 50-383, Poland
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