Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.

Fibroblast growth factor signalling: from development to cancer

Receptor specificity of the fibroblast growth factor family.

FGF23 is a unique member of the fibroblast growth factor (FGF) family because it acts as a hormone that derives from bone and regulates kidney functions, whereas most other family members are thought to regulate various cell functions at a local level. The renotropic activity of circulating FGF23 indicates the possible presence of an FGF23-specific receptor in the kidney. Here we show that a previously undescribed receptor conversion by Klotho, a senescence-related molecule, generates the FGF23 receptor. Using a renal homogenate, we found that Klotho binds to FGF23. Forced expression of Klotho enabled the high-affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wild-type mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signalling, we searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. These findings provide insights into the diversity and specificity of interactions between FGF and FGF receptors.

Klotho converts canonical FGF receptor into a specific receptor for FGF23

Fibroblast growth factors (FGFs) are small polypeptide growth factors, all of whom share in common certain structural characteristics, and most of whom bind heparin avidly. Many FGFs contain signal peptides for secretion and are secreted into the extracellular environment, where theycan bind to the heparan-like glycosaminoglycans (HLGAGs) of the extracellular matrix (ECM). From this reservoir, FGFs mayact directlyon target cells, or theycan be released through digestion of the ECM or the activityof a carrier protein, a secreted FGF binding protein. FGFs bind specific receptor tyrosine kinases in the context of HLGAGs and this binding induces receptor dimerization and activation, ultimatelyresulting in the activation of various signal transduction cascades. Some FGFs are potent angiogenic factors and most playimportant roles in embry onic development and wound healing. FGF signaling also appears to playa role in tumor growth and angiogenesis, and autocrine FGF signaling maybe particularlyimportant in the progression of steroid hormone-dependent cancers to a hormone-independent state.

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Fibroblast growth factors, their receptors and signaling.

Degeneracy, the ability of elements that are structurally different to perform the same function or yield the same output, is a well known characteristic of the genetic code and immune systems. Here, we point out that degeneracy is a ubiquitous biological property and argue that it is a feature of complexity at genetic, cellular, system, and population levels. Furthermore, it is both necessary for, and an inevitable outcome of, natural selection.

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Degeneracy and complexity in biological systems.

Fibroblast growth factor (FGF) receptor (FGFR) gene family consists of at least four receptor tyrosine kinases that transduce signals important in a variety of developmental and physiological processes related to cell growth and differentiation. Here we have characterized the binding of different FGFs to FGFR-4. Our results establish an FGF binding profile for FGFR-4 with aFGF having the highest affinity, followed by K-FGF/hst-1 and bFGF. In addition, FGF-6 was found to bind to FGFR-4 in ligand competition experiments. Interestingly, the FGFR-4 gene was found to encode only the prototype receptor in a region where both FGFR-1 and FGFR-2 show alternative splicing leading to differences in their ligand binding specificities and to secreted forms of these receptors. Ligands binding to FGFR-4 induced receptor autophosphorylation and phosphorylation of a set of cellular polypeptides, which differed from those phosphorylated in FGFR-1-expressing cells. Specifically, the FGFR-1-expressing cells showed a considerably more extensive tyrosine phosphorylation of PLC-gamma than the FGFR-4-expressing cells. Structural and functional specificity within the FGFR family exemplified by FGFR-4 may help to explain how FGFs perform their diverse functions.

Fibroblast growth factor receptor-4 shows novel features in genomic structure, ligand binding and signal transduction.

Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1.

Diverse receptors for fibroblast growth factors.

Fibroblast growth factors (FGFs) represent a group of polypeptide mitogens eliciting a wide variety of responses depending on the target cell type. The knowledge of the cell surface receptors mediating the effects of FGFs has recently expanded remarkably. Perhaps not surprisingly, the complexity of the FGF family and FGF induced responses is reflected in the diversity and redundancy of the FGF receptors. The molecular cloning of the signal transducing receptors for fibroblast growth factors has revealed a tyrosine kinase gene family with at least four members. Differential splicing and polyadenylation creates further diversity in the FGF receptor system. These numerous receptor forms have both distinct and redundant properties. We are only now beginning to understand how the different receptors are activated by the various FGFs and how they are expressed by various cells and tissues. FGF binding to the tyrosine kinase receptors needs the assistance of heparan sulphate side chains of proteoglycans present at the cell surface and in the extracellular matrix. As several other growth factors share the heparin binding property of FGFs, the dual receptor system for FGFs might be an example of a more widely used principle.

Structural and functional specificity of FGF receptors

We have previously cloned from K562 leukemia cells two novel fibroblast growth factor receptors (FGFR-3 and FGFR-4; J. Partanen et al. , EMBO J., 10 : 1347–1354, 1991). Here we have analyzed the mRNA expression of four different FGFRs, including the two novel genes in human leukemia cell lines. We show FGFR-1, FGFR-3, and FGFR-4 mRNAs in several leukemia cell lines at levels similar to those in solid tumor cell lines. Ligand cross-linking experiments indicate that K562 cells have receptors binding acidic FGF but not basic FGF. Expression of FGFRs in leukemia cells may reflect their presence on normal hematopoietic precursor cells or induction during leukemogenesis or cell culture.

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Satu Vainikka

Papers

Fibroblast growth factor receptor-4 shows novel features in genomic structure, ligand binding and signal transduction.

Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1.

Diverse receptors for fibroblast growth factors.

Structural and functional specificity of FGF receptors

Expression of Fibroblast Growth Factor Receptors in Human Leukemia Cells