成纤维细胞生长因子受体
成纤维细胞生长因子
信号转导
细胞生物学
受体酪氨酸激酶
受体
生物
酪氨酸激酶
MAPK/ERK通路
生物化学
作者
Natasha I. Edman,Rachel L. Redler,Ashish Phal,Thomas Schlichthaerle,Sanjay Srivatsan,Ali Etemadi,Seong Jin An,Andrew Favor,Devon Duron Ehnes,Zhe Li,Florian Praetorius,Max Gordon,Wei Yang,Brian Coventry,Derrick R. Hicks,Longxing Cao,Neville P. Bethel,Piper Heine,Analisa Murray,Stacey Gerben
标识
DOI:10.1101/2023.03.14.532666
摘要
Growth factors and cytokines signal by binding to the extracellular domains of their receptors and drive association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affects 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 MAPK pathway activation. The high specificity of the designed agonists reveal distinct roles for two FGFR splice variants in driving endothelial and mesenchymal cell fates during early vascular development. The ability to incorporate receptor binding domains and repeat extensions in a modular fashion makes our designed scaffolds broadly useful for probing and manipulating cellular signaling pathways.
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