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

Autor:	Edman NI; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA., Phal A; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA., Redler RL; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA., Schlichthaerle T; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Srivatsan SR; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Ehnes DD; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Etemadi A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Medical Biotechnology Department, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran., An SJ; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA., Favor A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Li Z; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Praetorius F; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Gordon M; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Vincent T; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA., Marchiano S; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Blakely L; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA., Lin C; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Yang W; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Coventry B; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Hicks DR; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Cao L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Bethel N; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA., Heine P; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Murray A; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Gerben S; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Carter L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Miranda M; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Negahdari B; Medical Biotechnology Department, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran., Lee S; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA., Trapnell C; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Allen Discovery Center for Cell Lineage Tracing, Seattle, WA 98109, USA., Zheng Y; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, Seattle WA 98109, USA., Murry CE; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Center for Cardiovascular Biology, University of Washington, Seattle WA 98109, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; Department of Medicine/Cardiology, University of Washington, Seattle WA 98195, USA., Schweppe DK; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Freedman BS; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98109, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; Kidney Research Institute, University of Washington School of Medicine, Seattle, WA 98109, USA., Stewart L; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Ekiert DC; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA., Schlessinger J; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA., Shendure J; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA; Allen Discovery Center for Cell Lineage Tracing, Seattle, WA 98109, USA., Bhabha G; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA., Ruohola-Baker H; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: hannele@uw.edu., Baker D; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA. Electronic address: dabaker@uw.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Jul 11; Vol. 187 (14), pp. 3726-3740.e43. Date of Electronic Publication: 2024 Jun 10.
DOI:	10.1016/j.cell.2024.05.025
Abstrakt:	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 Ca 2+ 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. Competing Interests: Declaration of interests L.S., D.B., N.I.E., T.S., A.E., A.F., W.Y., D.R.H., B.C., H.R.-B., A.P., R.L.R., G.B., and D.C.E. are coinventors on a patent application that has been filed by the University of Washington. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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