Fibroblast growth factor
Fibroblast growth factors (FGFs) are a family of 22 structurally related polypeptide growth factors that function as key signaling molecules in mammals, regulating essential cellular processes such as proliferation, differentiation, migration, survival, and apoptosis.[1] These proteins are evolutionarily conserved and play pivotal roles in embryonic development, tissue homeostasis, and repair by binding to specific receptors on target cells.[2] The FGF family is divided into seven subfamilies based on sequence homology and function: FGF1 (FGF1 and FGF2), FGF4 (FGF4, FGF5, FGF6), FGF7 (FGF3, FGF7, FGF10, FGF22), FGF8 (FGF8, FGF17, FGF18), FGF9 (FGF9, FGF16, FGF20), FGF15/19 (FGF19, FGF21, FGF23), and FGF11 (FGF11–FGF14, which are intracellular and non-secretory).[2] Most FGFs (the canonical or paracrine subtypes) require heparan sulfate proteoglycans as co-factors to bind and activate their receptors, while the endocrine FGFs (FGF19, FGF21, FGF23) depend on klotho proteins for specificity and activity.[1] Signaling occurs primarily through four tyrosine kinase receptors (FGFR1–FGFR4), each with alternative splice variants (e.g., IIIb and IIIc isoforms) that confer ligand specificity, leading to activation of downstream pathways including MAPK/ERK, PI3K/AKT, and PLCγ.[3] In health, FGFs are indispensable for organogenesis—such as limb, lung, and skeletal development—and adult physiological processes like angiogenesis, wound healing, metabolic regulation (e.g., glucose and phosphate homeostasis via FGF21 and FGF23), and tissue regeneration.[1] Dysregulation of FGF signaling contributes to numerous pathologies, including congenital disorders like achondroplasia and craniosynostosis (due to FGFR mutations), metabolic diseases such as obesity and chronic kidney disease, and cancers where amplified FGFRs or overexpressed FGFs promote tumorigenesis in organs like the bladder, breast, and prostate.[3] Ongoing research explores FGF-targeted therapies, including receptor inhibitors for oncology and recombinant FGFs for regenerative medicine.[1]Molecular Structure and Families
Protein Structure
Fibroblast growth factors (FGFs) are a family of secreted polypeptides typically comprising 150–300 amino acids, with mature proteins exhibiting molecular weights in the range of 17–34 kDa.[3] These proteins lack signal peptides in some cases, such as FGF1 and FGF2, leading to non-classical secretion mechanisms, while others possess cleavable N-terminal extensions.[3] The defining structural feature of FGFs is a conserved central core domain of approximately 120–130 amino acids that adopts a β-trefoil fold, characterized by 12 antiparallel β-strands (β1–β12) arranged into three β-sheet subdomains with approximate threefold rotational symmetry.[3] This compact fold is stabilized by hydrophobic interactions and includes heparin-binding sites primarily located in the β1–β2 loop and the β10–β12 region, which facilitate interactions with extracellular matrix components.[3] Divergent N- and C-terminal extensions flank this core, varying in length and sequence across family members to influence solubility, proteolytic stability, and biological specificity.[3] Most FGFs contain a conserved cysteine residue at position 83 (numbered relative to the core domain), which remains free in canonical members like FGF1 and FGF2, contributing to thermodynamic stability without forming intramolecular disulfides. In contrast, certain subfamilies, such as FGF8 and FGF19, feature an additional cysteine at position 66 that forms a disulfide bond with Cys83, enhancing thermostability by approximately 14 kJ/mol. For example, human FGF1 (UniProt P05230) has cysteines at positions 16, 83, and 117, none of which participate in disulfide bridges, preserving a monomeric structure essential for function.[4] Post-translational modifications further modulate FGF stability and activity. Phosphorylation sites, such as Ser116 in human FGF1, can alter protein half-life and signaling potency when mutated, as demonstrated by the S116R variant that enhances extracellular signal-regulated kinase phosphorylation.[5] Glycation, a non-enzymatic modification occurring under hyperglycemic conditions, targets lysine and arginine residues in FGF2, reducing angiogenic activity and signal transduction in endothelial cells by impairing heparin binding.[6] High-resolution crystal structures have elucidated these features; for instance, the X-ray structure of human FGF2 was determined at 1.9 Å resolution, revealing the β-trefoil core and solvent-exposed loops critical for ligand interactions.[7] These intrinsic structural motifs, particularly the β-trefoil fold and heparin-binding regions, underpin the capacity of FGFs to engage fibroblast growth factor receptors.[3]Classification into Families
In humans, the fibroblast growth factor (FGF) family consists of 22 ligands, encoded by Fgf genes and designated FGF1 through FGF14 and FGF16 through FGF23, with FGF15 being the ortholog of human FGF19 in mice. These ligands are classified into three main functional groups based on their modes of action and expression patterns: paracrine-acting FGFs, which primarily include FGF1–10, FGF16, FGF17, FGF18, FGF20, and FGF22 and function locally by binding cell-surface receptors; intracrine/autocrine-acting FGFs (FGF11–14), which lack signal peptides and exert effects intracellularly without secretion; and endocrine-acting FGFs (FGF19, FGF21, and FGF23), which circulate systemically and require co-receptors such as β-klotho for binding to fibroblast growth factor receptors (FGFRs).[1][8] Phylogenetically, the FGF family is divided into seven subfamilies based on sequence homology, evolutionary relationships, and conserved chromosomal synteny, reflecting their divergence from a common ancestor.[9] These subfamilies are: FGF1/2 (canonical paracrine); FGF4/5/6 (canonical paracrine, sharing over 40% amino acid sequence identity); FGF3/7/10/22 (paracrine, involved in epithelial-mesenchymal interactions); FGF8/17/18; FGF9/16/20 (paracrine, expressed in mesenchymal tissues); FGF11/12/13/14 (intracrine); and FGF19/21/23 (endocrine, with lower sequence similarity to others but distinct hormone-like functions).[10] This classification highlights evolutionary expansions, such as duplications within subfamilies, and underscores functional diversification, with paracrine members typically sharing a conserved β-trefoil core domain for receptor binding.[11] The Fgf genes are distributed across multiple chromosomes, often in clusters that preserve synteny across vertebrates, indicating coordinated regulation. For example, FGF1 is located on chromosome 5q31.3, FGF2 on 4q26, FGF3 and FGF4 on 11q13.3, and FGF23 on 12p13.32, with some subfamilies showing proximity such as the FGF3/4/19 cluster on 11q13.[12] Many FGF genes produce multiple isoforms through alternative splicing or other mechanisms, enhancing functional versatility; for instance, FGF2 generates four isoforms (18, 21, 22, and 24 kDa) via alternative translation initiation from a single mRNA, influencing subcellular localization and activity.[13]Receptors and Binding Mechanisms
Fibroblast Growth Factor Receptors (FGFRs)
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that transduce signals from fibroblast growth factors (FGFs) to regulate cellular processes such as proliferation and differentiation. The four principal members, FGFR1 through FGFR4, share a conserved structural architecture consisting of an extracellular ligand-binding domain, a single transmembrane helix, and an intracellular split tyrosine kinase domain. The extracellular domain comprises three immunoglobulin-like (Ig-like) loops, designated D1, D2, and D3, with D2 featuring a cysteine-rich region that contributes to receptor folding and stability through disulfide bond formation.[14] Mutations in the cysteine-rich domain of D2, such as those altering glycosylation sites, can enhance receptor stability and promote aberrant signaling, as observed in certain developmental disorders and cancers.[1] Alternative splicing primarily affects the third Ig-like domain (D3) in FGFR1, FGFR2, and FGFR3, generating two major isoforms: IIIb and IIIc. The IIIb isoform, encoded by exon 8 in FGFR1, FGFR2, and FGFR3, predominates in epithelial tissues and exhibits specificity for mesenchymal-derived FGFs, such as FGF7 (also known as keratinocyte growth factor) binding to FGFR2-IIIb. In contrast, the IIIc isoform, encoded by exon 9 in FGFR1, FGFR2, and FGFR3, is prevalent in mesenchymal cells and binds paracrine FGFs like FGF2. FGFR4 lacks this splicing variability and expresses only the IIIc-like form. The transmembrane domains of FGFRs harbor motifs that facilitate ligand-induced dimerization and oligomerization, enabling cooperative signaling.[14][1][15] FGFRs display distinct tissue-specific expression patterns that correlate with their physiological roles. FGFR1 is ubiquitously expressed across multiple tissues, including brain, kidney, and vascular endothelium, supporting broad developmental functions. FGFR2 is enriched in epithelial structures during embryogenesis, while FGFR3 is prominently expressed in cartilage and skeletal tissues, influencing bone growth. FGFR4 shows restricted distribution, such as in liver and skeletal muscle. The genes encoding these receptors are located on specific chromosomal sites: FGFR1 at 8p11.23, FGFR2 at 10q26.13, FGFR3 at 4p16.3, and FGFR4 at 5q35.2.[1][14] A fifth member, FGFR5 (also termed FGFRL1), diverges from the tyrosine kinase family by lacking an intracellular kinase domain and instead possessing a short histidine-rich tail; it functions as a modulator of FGFR1 signaling through interactions via its extracellular Ig-like domains. Heparan sulfate proteoglycans serve as essential co-receptors that enhance FGFR-FGF interactions.[16][14][17]| Receptor | Gene Location | Major Isoforms | Key Tissue Expression |
|---|---|---|---|
| FGFR1 | 8p11.23 | IIIb, IIIc | Ubiquitous (e.g., brain, kidney) |
| FGFR2 | 10q26.13 | IIIb, IIIc | Epithelial tissues |
| FGFR3 | 4p16.3 | IIIb, IIIc | Cartilage, bone |
| FGFR4 | 5q35.2 | IIIc only | Liver, skeletal muscle |
| FGFR5 | 4p16.3 | None (single) | Variable, regulatory |