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Reprogramming FGFR isoform specificity in FGF2 by deep mutational scanning
Yuga Okada1, Jumpei Morimoto1, Shinsuke Sando1,2
1Department of Chemistry and Biotechnology, The University of Tokyo 7-3-1 Hongo Bunkyo-ku Tokyo 113-8656 Japan ssando@chembio.t.u-tokyo.ac.jp.
Chemical Science
|August 6, 2026
Summary
Researchers engineered fibroblast growth factor 2 (FGF2) variants with altered fibroblast growth factor receptor (FGFR) specificity. Single-amino acid changes successfully reprogrammed receptor selectivity, enabling tailored FGF/FGFR signaling network control.
Area of Science:
- Molecular biology
- Biochemistry
- Signaling pathways
Background:
- The fibroblast growth factor (FGF) family and its seven fibroblast growth factor receptor (FGFR) isoforms form complex signaling networks.
- FGF2 has significant physiological roles and therapeutic potential, but its broad FGFR activation causes adverse effects.
- Engineering FGF ligands for controlled FGFR isoform specificity is crucial for therapeutic applications.
Purpose of the Study:
- To engineer FGF2 variants with altered FGFR isoform specificity.
- To identify key residues in the FGFR-binding interface that determine receptor specificity.
- To establish a framework for designing FGF ligands with tailored specificity.
Main Methods:
- Utilized mRNA display-based deep mutational scanning (DMS) to engineer FGF2 variants.
- Systematically evaluated residues within the FGFR-binding interface.
- Assessed the FGFR isoform specificity of engineered FGF2 variants.
Main Results:
- Successfully generated FGF2 variants with altered FGFR isoform specificity.
- Demonstrated that FGFR isoform specificity is malleable and can be reprogrammed.
- Identified single-amino acid substitutions as sufficient to alter receptor selectivity.
Conclusions:
- Receptor selectivity in FGF2 is tunable.
- Provided a method for rationally designing FGF ligands with specific FGFR isoform targeting.
- Advanced the understanding and control of FGF/FGFR signaling networks.
