{"language":[{"iso":"eng"}],"date_updated":"2023-11-07T12:21:58Z","type":"preprint","extern":"1","publication_status":"submitted","publication":"bioRxiv","oa_version":"Preprint","abstract":[{"lang":"eng","text":"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."}],"doi":"10.1101/2023.03.14.532666","author":[{"full_name":"Edman, Natasha I","first_name":"Natasha I","last_name":"Edman"},{"first_name":"Rachel L","full_name":"Redler, Rachel L","last_name":"Redler"},{"last_name":"Phal","first_name":"Ashish","full_name":"Phal, Ashish"},{"full_name":"Schlichthaerle, Thomas","first_name":"Thomas","last_name":"Schlichthaerle"},{"full_name":"Srivatsan, Sanjay R","first_name":"Sanjay R","last_name":"Srivatsan"},{"last_name":"Etemadi","full_name":"Etemadi, Ali","first_name":"Ali"},{"first_name":"Seong","full_name":"An, Seong","last_name":"An"},{"last_name":"Favor","full_name":"Favor, Andrew","first_name":"Andrew"},{"last_name":"Ehnes","first_name":"Devon","full_name":"Ehnes, Devon"},{"last_name":"Li","first_name":"Zhe","full_name":"Li, Zhe"},{"first_name":"Florian M","full_name":"Praetorius, Florian M","last_name":"Praetorius","id":"dfec9381-4341-11ee-8fd8-faa02bba7d62"},{"last_name":"Gordon","full_name":"Gordon, Max","first_name":"Max"},{"last_name":"Yang","first_name":"Wei","full_name":"Yang, Wei"},{"first_name":"Brian","full_name":"Coventry, Brian","last_name":"Coventry"},{"last_name":"Hicks","full_name":"Hicks, Derrick R","first_name":"Derrick R"},{"last_name":"Cao","full_name":"Cao, Longxing","first_name":"Longxing"},{"first_name":"Neville","full_name":"Bethel, Neville","last_name":"Bethel"},{"full_name":"Heine, Piper","first_name":"Piper","last_name":"Heine"},{"last_name":"Murray","first_name":"Analisa N","full_name":"Murray, Analisa N"},{"last_name":"Gerben","full_name":"Gerben, Stacey","first_name":"Stacey"},{"last_name":"Carter","first_name":"Lauren","full_name":"Carter, Lauren"},{"full_name":"Miranda, Marcos","first_name":"Marcos","last_name":"Miranda"},{"full_name":"Negahdari, Babak","first_name":"Babak","last_name":"Negahdari"},{"last_name":"Lee","first_name":"Sangwon","full_name":"Lee, Sangwon"},{"first_name":"Cole","full_name":"Trapnell, Cole","last_name":"Trapnell"},{"last_name":"Stewart","first_name":"Lance","full_name":"Stewart, Lance"},{"full_name":"Ekiert, Damian C","first_name":"Damian C","last_name":"Ekiert"},{"last_name":"Schlessinger","first_name":"Joseph","full_name":"Schlessinger, Joseph"},{"first_name":"Jay","full_name":"Shendure, Jay","last_name":"Shendure"},{"first_name":"Gira","full_name":"Bhabha, Gira","last_name":"Bhabha"},{"first_name":"Hannele","full_name":"Ruohola-Baker, Hannele","last_name":"Ruohola-Baker"},{"full_name":"Baker, David","first_name":"David","last_name":"Baker"}],"main_file_link":[{"url":"https://doi.org/10.1101/2023.03.14.532666","open_access":"1"}],"_id":"14294","title":"Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies","citation":{"ieee":"N. I. Edman <i>et al.</i>, “Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies,” <i>bioRxiv</i>. .","short":"N.I. Edman, R.L. Redler, A. Phal, T. Schlichthaerle, S.R. Srivatsan, A. Etemadi, S. An, A. Favor, D. Ehnes, Z. Li, F.M. Praetorius, M. Gordon, W. Yang, B. Coventry, D.R. Hicks, L. Cao, N. Bethel, P. Heine, A.N. Murray, S. Gerben, L. Carter, M. Miranda, B. Negahdari, S. Lee, C. Trapnell, L. Stewart, D.C. Ekiert, J. Schlessinger, J. Shendure, G. Bhabha, H. Ruohola-Baker, D. Baker, BioRxiv (n.d.).","ama":"Edman NI, Redler RL, Phal A, et al. Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies. <i>bioRxiv</i>. doi:<a href=\"https://doi.org/10.1101/2023.03.14.532666\">10.1101/2023.03.14.532666</a>","mla":"Edman, Natasha I., et al. “Modulation of FGF Pathway Signaling and Vascular Differentiation Using Designed Oligomeric Assemblies.” <i>BioRxiv</i>, doi:<a href=\"https://doi.org/10.1101/2023.03.14.532666\">10.1101/2023.03.14.532666</a>.","apa":"Edman, N. I., Redler, R. L., Phal, A., Schlichthaerle, T., Srivatsan, S. R., Etemadi, A., … Baker, D. (n.d.). Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies. <i>bioRxiv</i>. <a href=\"https://doi.org/10.1101/2023.03.14.532666\">https://doi.org/10.1101/2023.03.14.532666</a>","ista":"Edman NI, Redler RL, Phal A, Schlichthaerle T, Srivatsan SR, Etemadi A, An S, Favor A, Ehnes D, Li Z, Praetorius FM, Gordon M, Yang W, Coventry B, Hicks DR, Cao L, Bethel N, Heine P, Murray AN, Gerben S, Carter L, Miranda M, Negahdari B, Lee S, Trapnell C, Stewart L, Ekiert DC, Schlessinger J, Shendure J, Bhabha G, Ruohola-Baker H, Baker D. Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies. bioRxiv, <a href=\"https://doi.org/10.1101/2023.03.14.532666\">10.1101/2023.03.14.532666</a>.","chicago":"Edman, Natasha I, Rachel L Redler, Ashish Phal, Thomas Schlichthaerle, Sanjay R Srivatsan, Ali Etemadi, Seong An, et al. “Modulation of FGF Pathway Signaling and Vascular Differentiation Using Designed Oligomeric Assemblies.” <i>BioRxiv</i>, n.d. <a href=\"https://doi.org/10.1101/2023.03.14.532666\">https://doi.org/10.1101/2023.03.14.532666</a>."},"date_created":"2023-09-06T12:31:49Z","month":"03","article_processing_charge":"No","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","date_published":"2023-03-15T00:00:00Z","oa":1,"year":"2023","status":"public","day":"15"}