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Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies

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...

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Autores principales: Edman, Natasha I, Redler, Rachel L, Phal, Ashish, Schlichthaerle, Thomas, Srivatsan, Sanjay R, Etemadi, Ali, An, Seong J, Favor, Andrew, Ehnes, Devon, Li, Zhe, Praetorius, Florian, Gordon, Max, Yang, Wei, Coventry, Brian, Hicks, Derrick R., Cao, Longxing, Bethel, Neville, Heine, Piper, Murray, Analisa, Gerben, Stacey, Carter, Lauren, Miranda, Marcos, Negahdari, Babak, Lee, Sangwon, Trapnell, Cole, Stewart, Lance, Ekiert, Damian C., Schlessinger, Joseph, Shendure, Jay, Bhabha, Gira, Ruohola-Baker, Hannele, Baker, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055045/
https://www.ncbi.nlm.nih.gov/pubmed/36993355
http://dx.doi.org/10.1101/2023.03.14.532666
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author Edman, Natasha I
Redler, Rachel L
Phal, Ashish
Schlichthaerle, Thomas
Srivatsan, Sanjay R
Etemadi, Ali
An, Seong J
Favor, Andrew
Ehnes, Devon
Li, Zhe
Praetorius, Florian
Gordon, Max
Yang, Wei
Coventry, Brian
Hicks, Derrick R.
Cao, Longxing
Bethel, Neville
Heine, Piper
Murray, Analisa
Gerben, Stacey
Carter, Lauren
Miranda, Marcos
Negahdari, Babak
Lee, Sangwon
Trapnell, Cole
Stewart, Lance
Ekiert, Damian C.
Schlessinger, Joseph
Shendure, Jay
Bhabha, Gira
Ruohola-Baker, Hannele
Baker, David
author_facet Edman, Natasha I
Redler, Rachel L
Phal, Ashish
Schlichthaerle, Thomas
Srivatsan, Sanjay R
Etemadi, Ali
An, Seong J
Favor, Andrew
Ehnes, Devon
Li, Zhe
Praetorius, Florian
Gordon, Max
Yang, Wei
Coventry, Brian
Hicks, Derrick R.
Cao, Longxing
Bethel, Neville
Heine, Piper
Murray, Analisa
Gerben, Stacey
Carter, Lauren
Miranda, Marcos
Negahdari, Babak
Lee, Sangwon
Trapnell, Cole
Stewart, Lance
Ekiert, Damian C.
Schlessinger, Joseph
Shendure, Jay
Bhabha, Gira
Ruohola-Baker, Hannele
Baker, David
author_sort Edman, Natasha I
collection PubMed
description 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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spelling pubmed-100550452023-03-30 Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies Edman, Natasha I Redler, Rachel L Phal, Ashish Schlichthaerle, Thomas Srivatsan, Sanjay R Etemadi, Ali An, Seong J Favor, Andrew Ehnes, Devon Li, Zhe Praetorius, Florian Gordon, Max Yang, Wei Coventry, Brian Hicks, Derrick R. Cao, Longxing Bethel, Neville Heine, Piper Murray, Analisa Gerben, Stacey Carter, Lauren Miranda, Marcos Negahdari, Babak Lee, Sangwon Trapnell, Cole Stewart, Lance Ekiert, Damian C. Schlessinger, Joseph Shendure, Jay Bhabha, Gira Ruohola-Baker, Hannele Baker, David bioRxiv Article 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. Cold Spring Harbor Laboratory 2023-03-15 /pmc/articles/PMC10055045/ /pubmed/36993355 http://dx.doi.org/10.1101/2023.03.14.532666 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Edman, Natasha I
Redler, Rachel L
Phal, Ashish
Schlichthaerle, Thomas
Srivatsan, Sanjay R
Etemadi, Ali
An, Seong J
Favor, Andrew
Ehnes, Devon
Li, Zhe
Praetorius, Florian
Gordon, Max
Yang, Wei
Coventry, Brian
Hicks, Derrick R.
Cao, Longxing
Bethel, Neville
Heine, Piper
Murray, Analisa
Gerben, Stacey
Carter, Lauren
Miranda, Marcos
Negahdari, Babak
Lee, Sangwon
Trapnell, Cole
Stewart, Lance
Ekiert, Damian C.
Schlessinger, Joseph
Shendure, Jay
Bhabha, Gira
Ruohola-Baker, Hannele
Baker, David
Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
title Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
title_full Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
title_fullStr Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
title_full_unstemmed Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
title_short Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
title_sort modulation of fgf pathway signaling and vascular differentiation using designed oligomeric assemblies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055045/
https://www.ncbi.nlm.nih.gov/pubmed/36993355
http://dx.doi.org/10.1101/2023.03.14.532666
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