Fibroblast Growth Factor Signaling in Health and Disease

Fibroblast growth factors (FGFs) and their tyrosine kinase receptors (FGFRs) form a complex signalling network vital to embryonic development, tissue homeostasis, repair processes and metabolic regulation. FGFs operate through paracrine, autocrine and endocrine modes, engaging FGFRs with the assistance of cofactors such as heparan sulphate proteoglycans and Klotho proteins. Ligand binding induces receptor dimerisation and kinase activation, triggering downstream cascades including MAPK, PI3K–AKT and PLCγ pathways. In health, FGF signalling orchestrates organogenesis, angiogenesis, skeletal formation and wound healing. Dysregulation, through mutations, aberrant expression or altered glycosylation, underpins a spectrum of disorders spanning skeletal dysplasias, cardiovascular disease, metabolic syndromes and malignancies. Advances in structural biology and molecular engineering have refined our understanding of receptor activation, coreceptor engagement and post-translational modulation, offering new avenues for targeted therapies.

Research from Nature Portfolio

Recent structural studies have resolved cryo-electron microscopy architectures of endocrine FGF–FGFR complexes incorporating αKlotho and heparan sulphate, revealing an asymmetric mode of receptor dimerisation that challenges the canonical symmetric paradigm and informs rational design of signalling modulators. Investigations into fibroblast growth factor 18 have demonstrated its cardioprotective role in pressure overload-induced hypertrophy, mediated by FGFR3-driven activation of the FYN kinase and suppression of oxidative stress via downregulation of NOX4. Seminal mechanistic work on FGFR dynamics established that unliganded receptor dimers exist in basal states and that ligand binding alters transmembrane helix separation to modulate kinase phosphorylation, elucidating multiple active conformations relevant to disease-causing mutations.

Fibroblast Growth Factor Signaling in Health and Disease publication trend

The graph below shows the total number of articles in fibroblast growth factor signaling in health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Fibroblast growth factor (FGF): A family of signalling proteins that regulate cell proliferation, differentiation and tissue repair.

FGF receptor (FGFR): A transmembrane tyrosine kinase that binds FGFs to initiate intracellular signalling cascades.

Coreceptor: A molecule such as heparan sulphate proteoglycan or Klotho that associates with FGFR to enhance ligand binding and activation.

Dimerisation: The pairing of two receptor molecules, enabling transphosphorylation and downstream signal transduction.

Glycosylation: The enzymatic attachment of sugar moieties to proteins, modulating their stability, localisation and interactions.

Valency: The number of ligand-binding sites within a signalling assembly that influences receptor activation dynamics.

References

1. Structural basis for FGF hormone signalling. Nature (2023).
2. Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies. Cell (2024).
3. Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice. Nature Communications (2023).
4. Glycosylation of FGF/FGFR: An underrated sweet code regulating cellular signaling programs. Cytokine & Growth Factor Reviews (2024).
5. FGF/FGFR signaling in health and disease. Signal Transduction and Targeted Therapy (2020).
6. Mechanism of FGF receptor dimerization and activation. Nature Communications (2016).