Increased thermal stability of FGF10 leads to ectopic signaling during development

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F25%3A00636904" target="_blank" >RIV/67985904:_____/25:00636904 - isvavai.cz</a>

Alternative codes found

RIV/68378050:_____/25:00636904 RIV/00216224:14110/25:00141103 RIV/00159816:_____/25:00082445

Result on the web

<a href="https://link.springer.com/article/10.1007/s00018-025-05681-1" target="_blank" >https://link.springer.com/article/10.1007/s00018-025-05681-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1007/s00018-025-05681-1" target="_blank" >10.1007/s00018-025-05681-1</a>

Result language

angličtina

Original language name

Increased thermal stability of FGF10 leads to ectopic signaling during development

Original language description

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 degrees C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 degrees 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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10601 - Cell biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cellular and Molecular Life Sciences

ISSN

1420-682X

e-ISSN

1420-9071

Volume of the periodical

82

Issue of the periodical within the volume

1

Country of publishing house

CH - SWITZERLAND

Number of pages

24

Pages from-to

167

UT code for WoS article

001472115300002

EID of the result in the Scopus database

2-s2.0-105003276698