Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.
Cell
; 187(14): 3726-3740.e43, 2024 Jul 11.
Article
em En
| MEDLINE
| ID: mdl-38861993
ABSTRACT
Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Diferenciação Celular
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Receptores de Fatores de Crescimento de Fibroblastos
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Fatores de Crescimento de Fibroblastos
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2024
Tipo de documento:
Article