New developments in the biology of fibroblast growth factors

Abstract

The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltage-gated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology Congenital Diseases > Stem Cells and Development Cancer > Stem Cells and Development.

Keywords: fibroblast growth factors; organogenesis; receptor tyrosine kinase; regeneration; tyrosine kinase inhibitors.

FIGURE 1

The FGF and FGFR family. (a) Phylogenetic analysis shows the organization of the 22 Fgf genes into seven subfamilies. Branch lengths represent the evolutionary distance between each gene. Canonical FGFs include the Fgf1, Fgf4, Fgf7, Fgf8, and Fgf9 subfamilies that interact with the cofactor heparin/heparan sulfate (HS) for binding and activation of different splice variants (b and c) of the four FGFRs. The Fgf15/19 subfamily members encode endocrine FGFs (eFGFs), which use αKlotho (KL) or βKlotho (KLB) as the primary cofactors for binding and activation of FGFRs. FGF15/19 can also interact with Lactase-like Klotho (LCTL) also called Klotho-LPH related protein (KLPH) or γKlotho. eFGFs have lower affinity for HS but still required HS for optimal receptor binding. The Fgf11 subfamily genes encode intracellular FGFs (iFGFs), which are thought to be non-signaling proteins serving as regulators of voltage-gated sodium (Nav) channels and other molecules. Recent data open the possibility that iFGFs can activate FGFRs under certain conditions. (b) Diagram showing FGFR domain structures. The FGFR extracellular domain includes three immunoglobulin-like domains (I, II, and III) linked with disulfide (S–S) bonds and an acidic region (A), a transmembrane domain (TM), and two intracellular tyrosine kinase domains (TK1 and TK2). SP indicates a cleavable secreted signal sequence. Of the four Fgfr genes, Fgfr1–Fgfr3 generate two major splice variants in immunoglobulin-like domain III, referred to as IIIb and IIIc, which are essential determinants of ligand-binding specificity. (c) Schematic showing the relative orientation of an active signaling complex with a canonical FGF ligand, HS, and an FGFR forming a 2:2:2 dimer. (d) Diagram of FGFRL1/FGFR5 protein structure. FGFRL1 has a similar extracellular domain structural to other FGFRs with three extracellular immunoglobulin-like domains (I, II, and III) and a transmembrane domain (TM). Unlike other FGFRs, FGFRL1 has a short intracellular tail with no tyrosine kinase domain. SP indicates a cleavable secreted signal sequence

FIGURE 2

FGF secretion, dimerization, and receptor shedding regulate the availability and activity of FGFs. (a) Unconventional secretion of FGF2 (adapted from Zacherl et al., 2015). ATP1A1, the α1-chain of Na/K-ATPase, interacts with FGF2 and recruits it to the inner plasma membrane, and promotes oligomerization. FGF2 oligomerization requires phosphatidylinositol 4,5-bisphosphate and FGF2 surface cysteines. Phosphorylation of FGF2 by Tec Kinase further promotes membrane insertion of FGF2 oligomers to form a membrane pore. FGF2, which is released into the extracellular space is bound and sequestered by cell surface HSPGs. (b) Dimerization of the FGF9 subfamily increases affinity for HS and prevents receptor binding by blocking the receptor-binding interface (blue). Mutations in FGF9 prevent homodimerization, decrease affinity for HS, and increase ligand diffusion. Only FGF9 monomers are able to interact with FGFRs. (c) Proteolytic cleavage of FGFRs by ADAM proteases 10 and 17 can release a soluble extracellular domain of the receptor that has the ability to bind and sequester FGF ligands

FIGURE 3

Cell surface and extracellular molecules that interact with FGF ligands and receptors. FGFR showing immunoglobulin-like domains I, II, and III and intracellular tyrosine kinase domains, TK1 and TK2. FGF ligands bind to the heparan sulfate (HS) chains that decorate heparan sulfate proteoglycans (HSPGs). FGF ligands also bind to long pentraxin 3 (PTX3), FGF binding proteins (FGFBP), and latent TGFβ binding protein 2 (LTBP2). FGFR–FGF interactions are stabilized by HS, α, β, and ɣ Klotho, Anosmin 1 (ANOS1), and fibronectin leucine-rich transmembrane proteins (FLRTs). ANOS1 can form a complex with FGFR and L1 cell adhesion molecule (L1CAM). Cell adhesion molecules, including neural cell adhesion molecule (NCAM) and N-cadherin (CDH2) can activate low-level FGFR signaling independent of FGF ligands. Inorganic phosphate (Pi) can directly activate FGFR signaling independent of FGF ligands. FGF receptor-like 1 (FGFRL1) lacks an intracellular tyrosine kinase domain and is involved in cell adhesion and may act as a decoy receptor through binding FGF ligands. Relative strength of signaling is indicated below each receptor