Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology - PubMed (original) (raw)

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Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology

Artur A Belov et al. Cold Spring Harb Perspect Biol. 2013.

Abstract

Fibroblast growth factors (FGFs) signal in a paracrine or endocrine fashion to mediate a myriad of biological activities, ranging from issuing developmental cues, maintaining tissue homeostasis, and regulating metabolic processes. FGFs carry out their diverse functions by binding and dimerizing FGF receptors (FGFRs) in a heparan sulfate (HS) cofactor- or Klotho coreceptor-assisted manner. The accumulated wealth of structural and biophysical data in the past decade has transformed our understanding of the mechanism of FGF signaling in human health and development, and has provided novel concepts in receptor tyrosine kinase (RTK) signaling. Among these contributions are the elucidation of HS-assisted receptor dimerization, delineation of the molecular determinants of ligand-receptor specificity, tyrosine kinase regulation, receptor cis-autoinhibition, and tyrosine trans-autophosphorylation. These structural studies have also revealed how disease-associated mutations highjack the physiological mechanisms of FGFR regulation to contribute to human diseases. In this paper, we will discuss the structurally and biophysically derived mechanisms of FGF signaling, and how the insights gained may guide the development of therapies for treatment of a diverse array of human diseases.

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Figures

Figure 1.

Figure 1.

FGF signaling in the liver and adipose tissue. (A) The paracrine FGF signaling loop in the liver. FGFs are expressed in both the epithelial or mesenchymal tissue, and signal in a paracrine fashion through their cognate receptors, which are expressed in the opposite tissues. Shown are two examples of paracrine ligands, FGF8 and FGF10, which signal exclusively in an epithelial-to-mesenchyme and mesenchyme-to-epithelial manner, respectively. (B) Comparison of the crystal structures of FGF2 (PDB: 1FQ9) and FGF19 (PDB: 2P23) provides the structural basis for the low affinity of endocrine ligands for HS. (C) Comparison of the binding interactions of FGF2, FGF19, FGF21, and FGF23 with HS using surface-plasmon resonance spectroscopy. The low affinity of FGF19 family members (such as FGF21) allows them to permeate freely through the HS-dense intercellular space and enter into the blood. This enables them to act as hormones in target tissues in which α/β Klotho coreceptors are expressed (top panel in part A).

Figure 2.

Figure 2.

Structural features of a prototypical FGF receptor and FGF-conserved FGF–FGFR contacts. (A) The X-ray structure of FGF2–FGFR1c (PDB: 1FQ9) and an NMR structure of D1 (PDB: 2CR3) were linked arbitrarily with a modeled D1–D2 linker to construct a model of a full-length FGF receptor. The acid box is red and the HS binding region in the FGF2–FGFR1c complex is blue. FGFR1c and FGF2 are cyan and salmon, respectively. The alternatively spliced portion of D3 is magenta. (B) Prototypical contacts (PDB: 1FQ9) between the ligand and receptor D2 are illustrated. Dashed lines denote hydrogen bonds. Hydrophobic contacts are indicated using transparent surfaces. Oxygen and nitrogen atoms are red and blue, respectively, hereafter. (C) The conserved hydrogen bonds at the interface between the D2–D3 linker and D3 of the FGFR and FGF ligand as observed in the FGF10–FGFR2b structure (PDB: 1NUN). The dashed box within panel C highlights the hydrogen bonds between the D2–D3 linker of FGFR and FGF.

Figure 3.

Figure 3.

General and FGF8-specific modes of FGF–FGFR binding. FGF1 and FGF10 in complex with FGFR2b are illustrated with the alternatively spliced regions of D3 shown in slate. FGF2 and FGF8b in complex with FGFR2c are also illustrated, with the alternatively spliced regions of D3 in pink. FGF1, FGF10, FGF2, and FGF8b are light pink, gray, wheat, and salmon, respectively. The constant regions of FGFRs are lime green. Each subpanel illustrates the specific contacts the ligands make with D3. In the subpanels A and B, the β4 strands from FGF1 and FGF10 are made transparent to allow for the visualization of the π-cation interactions at the βF–βG loop outside of the D3 cleft.

Figure 4.

Figure 4.

HS/Klotho-assisted FGFR dimerization. (A) FGF2–FGFR1c–HS ternary complex (PDB:1FQ9). FGF2 (cyan) and FGFR1c (salmon) are shown in ribbons, while HS is depicted in the surface representation (red). The top panel illustrates the direct receptor–receptor contacts. In the middle and bottom panels, secondary receptor–ligand contacts are shown for the 2:2 FGF2–FGFR1c and 2:2 FGF10–FGFR2b dimers, respectively. (B) A working model for the endocrine FGF–FGFR–Klotho signaling dimer constructed by the superimposition of the FGF23 structure (PDB: 2P23) onto FGF2 in the FGF2–FGFR1c–HS ternary complex (PDB:1FQ9). The two Klotho (KL) domains, shown in two shades of gray, were modeled using the crystal structure of myrosinase (PDB: 1E6S). The carboxy tail of FGF23 is also modeled to show that it engages a composite site created at the FGFR–Klotho interface.

Figure 5.

Figure 5.

Comparison of FGFR2 kinases in the unphosphorylated and A-loop phosphorylated states. (A) The inhibitory network of hydrogen bonds, termed the “molecular brake,” at the kinase hinge/interlobe region of the unphosphorylated low-activity FGFR2 kinase (PDB: 2PSQ, cyan). (B) Disengagement of the molecular brake in the A-loop phosphorylated activated FGFR2 kinase (PDB: 2PVF, gray). (C) The unphosphorylated A-loop conformation and select amino acids are shown. (D) The phosphorylated A-loop is held in an active conformation by hydrogen bonds between the phosphate moiety of phosphorylated A-loop tyrosine and basic residues (Arg-?? and Lys-??) within the A-loop. Note that on phosphorylation of A-loop Y656 and Y657, the A-loop undergoes a major conformational change as evidenced by the pistonlike conformational switch in the orientation of I654 and N662.

Figure 6.

Figure 6.

Comparison of the carboxy-tail and kinase-insert _trans_-phosphorylation complexes. (A) The crystal structure of FGFR2 kinases caught in the act of _trans_-phosphorylation on carboxy-tail tyrosine Tyr-769 (PDB: 3CLY). The enzyme-acting kinase is cyan, and the substrate kinase is salmon. The αI helix and kinase insert are green, with the amino to carboxy polarity indicated with arrows. (B) The kinase-insert _trans_-phosphorylation complex (PDB: 3GQI) is colored as in A. Note that the kinase insert Tyr-583 has been mutated to phenylalanine. Compared to the carboxy-tail tyrosine _trans_-phosphorylation complex, there are fewer interactions between the enzyme and the substrate in the kinase-insert tyrosine _trans_-phosphorylation complex.

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