The FGF family: biology, pathophysiology and therapy

Abstract

The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.

Figure 1. structural features of fibroblast growth factors (FgFs)

a | FGF1, showing its 12 antiparallel β-sheets and amino and carboxyl termini. b | The 18 FGFs, grouped according to subfamily. The sequence alignment in the region of the divergent N terminus proximal to the β-trefoil core is given. The β1 strand of FGF1 is provided to indicate the limit of the N terminus. c | FGF19 superimposed onto FGF2 from the FGF2–FGF receptor 1–heparin ternary structure (Protein Data Bank). FGF2 and FGF19 are rendered as ribbons and heparin is shown as sticks: oxygen (red), nitrogen (blue), carbon (beige), and sulphur (green) atoms are shown. The core regions of both ligands are coloured grey, and the heparin binding regions of FGF2 and FGF19 are coloured cyan and orange, respectively. Heparin from 1FQ9 clashes with the ridges in the heparin binding region of FGF19. To eliminate these clashes, heparin must translocate away from FGF19 but, in doing so, crucial contacts between heparin and the FGF19 backbone cannot be made. The weakened heparin binding observed in the FGF19 subfamily members is responsible for their endocrine behaviour.

Figure 2. structural features of fibroblast growth factor receptors (FgFrs)

a | A schematic of the FGFR structure. b | The sequence alignment of the seven main FGFRs in the region of the βC′–βE loop, including the βC′ and βE strands. The vertical green bar divides the unspliced portion of the receptor at the left from the spliced portion that follows. c | A superimposition of the D3 domains of solved FGF–FGFR complex structures. FGF2–FGFR2c is shown in red, FGF8–FGFR2c is shown in purple, FGF1–FGFR1c is shown in blue, FGF1–FGFR2b is shown in green, FGF1–FGFR3c is shown in black, FGF1–FGFR2c is shown in brown, FGF2–FGFR1c is shown in pink, FGF3–FGFR2b is shown in grey and FGF10–FGFR2b is shown in cyan. The variation in the conformation of the βC′–βE loop between the structures as it interacts with divergent amino termini is evident. The plasticity of this loop is a major determinant of FGF–FGFR binding specificity.

Figure 3. Fibroblast growth factor receptor (FgFr) signalling

Structurally unresolved regions are shown as grey lines. Amino-terminal and carboxy-terminal lobes of the kinase domain are coloured green and red, respectively. The two major intracellular targets, phospholipase (PLC)γ1 and FGFR substrate 2α (FRS2α), are shown. A loop, activation loop; GRB2, growth factor receptor bound 2; HS, heparan sulphate; IP₃, inositol-1,4,5-trisphosphate; MAPK, mitogen-activated protein kinase; MAPKK, mitogen-activated protein kinase kinase; PH, pleckstrin homology domain; PIP₂, phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; PTB, phosphotyrosine binding domain; PTK, protein tyrosine kinase; SH, Src homology domain. Figure is modified, with permission, from REF. (2005) Elsevier Science.

Figure 4. The physiology of fibroblast growth factor 19 (FgF19), FgF21 and FgF23

a | Bile acids activate the FXR receptor in the intestine, leading to expression of FGF19 in the ileum. FGF19 circulates to the liver, where it acts through FGF receptor 4 (FGFR4) to inhibit bile acid synthesis and lipogenesis. b | FGF21 mediates the fasting response and is regulated by peroxisome proliferator-activated receptor-α (PPARα) and PPARγ in liver and adipose tissue, respectively. The biology of FGF21 in model systems and humans is still being elucidated, but among its many functions are increasing glucose uptake in adipose tissue, improving β-cell function, inhibiting glucagon secretion, increasing ketogenesis and regulating lipolysis and lipogenesis in a complex manner. FGF21 is expressed in liver, adipose and pancreatic tissue. It acts primarily on adipose tissue. The effects of FGF21 on liver function are probably accomplished through indirect mechanisms as it does not signal through FGFR4. c | FGF23 production is upregulated in bone in response to high serum phosphate and vitamin D levels. FGF23 then circulates to the parathyroid gland, intestine and kidney. In the intestine, FGF23 downregulates 1α-hydroxylase so as to reduce the levels of activated vitamin D, thereby inhibiting absorption of phosphate from the diet. The repression of parathyroid hormone (PTH) by FGF23 also helps to downregulate 1α-hydroxylase. In the kidney, FGF23 inhibits Na⁺–phosphate ion co-transport and thus increases excretion of phosphate. CYP7A1, cytochrome P450 7A1; SCD1, stearoyl CoA desaturase 1.