Journal Article

Exploring mechanisms of FGF signalling through the lens of structural biology

Mohammadi, Moosa, Goetz, Regina

2013

Overview

Key Points Fibroblast growth factor (FGF) signalling controls a myriad of processes in embryonic development and in tissue homeostasis and metabolism in the adult. Recent structural studies have provided a glimpse of the complexity of molecular control that is in place to fine-tune this signalling system to enable it to produce specific signalling outputs in diverse biological contexts. The interaction of FGFs with heparan sulphate glycosaminoglycan chains of heparan sulphate proteoglycans in the pericellular and extracellular matrix defines their mode of action, that is, whether an FGF acts in a paracrine or endocrine fashion. It also determines the shape of gradient formed by a paracrine FGF ligand in the extracellular matrix, which in turn is a determinant of the biological response to that ligand. In addition to mechanisms common to all FGFs, such as the interaction with heparan sulphate, the biological activity of individual ligands or ligand subfamilies is regulated by mechanisms unique to these ligands: amino-terminal alternative splicing controls the activity of FGF8 subfamily ligands; homodimerization autoinhibits the activity of FGF9 subfamily ligands; and site-specific proteolytic cleavage inactivates the phosphaturic hormone FGF23. Alternative splicing in the extracellular immunoglobulin-like domain 3 (D3) of FGF receptor 1 (FGFR1), FGFR2 and FGFR3 primarily determines the ligand-binding specificity of these receptors. This splicing event is fundamental to the establishment of directional paracrine FGF signalling between the epithelium and the mesenchyme, which underlies the coordinated cellular processes that govern organ development. Klotho co-receptors convert FGFRs into specific receptors for endocrine FGFs by a dual mechanism; these co-receptors not only enhance the binding affinity of FGFRs for endocrine FGFs but concomitantly suppress the binding of paracrine FGFs to FGFRs. The finding that heparan sulphate is dispensable for signalling by endocrine FGFs implies that Klotho co-receptors also promote FGFR dimerization upon endocrine FGF binding, which is required for FGFR activation. The structural findings suggest that there may be no functional redundancy among FGF ligands, and genetic data support this conclusion. Hence, future studies should concentrate on identifying novel ligand-specific functions of FGF signalling. Structural data has provided insight into the molecular mechanisms that modulate fibroblast growth factor (FGF) signalling to generate distinct biological outputs in development, tissue homeostasis and metabolism. Mechanisms include alternative splicing of ligand and receptor, homodimerization and site-specific proteolytic cleavage of ligand, and interaction of ligand and receptor with heparan sulphate and Klotho co-receptors. Fibroblast growth factors (FGFs) mediate a broad range of functions in both the developing and adult organism. The accumulated wealth of structural information on the FGF signalling pathway has begun to unveil the underlying molecular mechanisms that modulate this system to generate a myriad of distinct biological outputs in development, tissue homeostasis and metabolism. At the ligand and receptor level, these mechanisms include alternative splicing of the ligand (FGF8 subfamily) and the receptor (FGFR1–FGFR3), ligand homodimerization (FGF9 subfamily), site-specific proteolytic cleavage of the ligand (FGF23), and interaction of the ligand and the receptor with heparan sulphate cofactor and Klotho co-receptor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/1645/1946 / 631/337/474 / 86 / Alternative Splicing / Binding sites / Biochemistry / Biomedical and Life Sciences / Cancer Research / Cell Biology / Crystal structure / Developmental Biology / Fibroblast Growth Factor 8 - genetics / Fibroblast Growth Factor 8 - metabolism / Fibroblast Growth Factor 9 - metabolism / Fibroblast growth factors / Fibroblast Growth Factors - chemistry / Fibroblast Growth Factors - metabolism / Fibroblasts / Glucuronidase - metabolism / Growth factors / Heparitin Sulfate - metabolism / Homeostasis / Kinases / Life Sciences / Ligands / Metabolism / Physiological aspects / Proteins / Receptor, Fibroblast Growth Factor, Type 1 - genetics / Receptor, Fibroblast Growth Factor, Type 1 - metabolism / Receptor, Fibroblast Growth Factor, Type 2 - genetics / Receptor, Fibroblast Growth Factor, Type 2 - metabolism / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Receptor, Fibroblast Growth Factor, Type 3 - metabolism / Receptors, Fibroblast Growth Factor - metabolism / review-article / Signal Transduction / Stem Cells / Sulfates