In the 1980s, researchers isolated fibroblast growth factors (FGFs) from the brain and pituitary gland. Originally identified for their capacity to trigger fibroblast mitosis, these FGFs are versatile mitogenic factors. They act as peptide ligands that can exert their impact through autocrine, paracrine, or endocrine pathways. FGF primarily operates via the signal axis mediated by fibroblast growth factor receptors (FGFR), either stimulating or sustaining specific cellular functions associated with metabolism, tissue homeostasis, and development. FGFs play a pivotal role in overseeing cell proliferation, differentiation, survival, migration, and metabolism.
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The FGF Family
The FGF family comprises at least 20 members, designated as FGF-1 through FGF-20. However, acidic FGF and basic FGF are commonly referred to as FGF1 and FGF2, respectively, while keratinocyte growth factor (KGF) is a common name for FGF7. Acidic FGF (aFGF) and basic FGF (bFGF) serve as prototype members of the FGF family, named for their distinct isoelectric points. They share 55% homology in amino acid sequence and exhibit similar sizes. Based on phylogenetic analysis, FGFs can be categorized into seven subfamilies. Some studies propose the existence of eight FGF families, with FGF3 forming a separate "family" consisting of a single member.
FGFs can be categorized into several subfamilies based on biochemical functions, sequence similarity, and evolutionary relationships: the paracrine FGFs, including FGF1, FGF4, FGF7, FGF8, and FGF9, which act as signaling molecules secreted into the extracellular space; the endocrine FGFs, represented by FGF19, which function as hormones; and the intracrine FGFs, exemplified by FGF11, which operate within the cell.
FGF1 subfamily consists of FGF1 and FGF2. These fibroblast growth factors lack a classical secretion signal peptide but can easily translocate from the cell through the cell membrane. Some studies suggest that extracellular FGF1 crosses the cell membrane, moves through the cytoplasm, and enters the nucleus. The primary functions of FGF1 are to regulate the cell cycle, cell differentiation, survival, and apoptosis. FGF1 is the only fibroblast growth factor that can activate all splice variants of fibroblast growth factor receptors.
FGF4 subfamily: Comprising FGF4, FGF5, and FGF6, all members of this subfamily are secreted proteins with cleavable N-terminal signal peptides. They act as extracellular proteins to regulate biological effects by binding and activating FGF receptors. These FGFs activate splice variants of FGF receptors 1-3 and the c isoform of FGF receptor 4.
FGF7 subfamily: The FGF7 family includes FGF3, FGF7, FGF10, and FGF22. These fibroblast growth factors preferentially activate the b isoform splice variants of FGF receptors 2 and FGF receptors 3, and also activate the b isoform splice variants of FGF receptor 1.
FGF8 subfamily: The FGF8 subfamily consists of FGF8, FGF17, and FGF18. Members of this subfamily have one N-terminal cleavage signal peptide. These FGFs activate splice variants of FGF receptors 1-3 and the c isoform of FGF receptor 4.
FGF9 subfamily: The FGF9 subfamily includes FGF9, FGF16, and FGF20. This subfamily lacks a typical N-terminal signal peptide but contains an internal hydrophobic sequence, serving as a non-cleavable signal to transmit signals to the endoplasmic reticulum. This subfamily possesses unique activation capabilities, activating not only the c isoform splice variants of FGF receptors 4 and FGF receptors 1, 2, 3 but also activating the b isoform splice variant of FGF receptor 3.
FGF Signaling
FGFs serve as signaling molecules binding and activating FGFRs. Activated FGFRs initiate signaling cascades by recruiting specific molecules to the phosphorylated tyrosine on the receptor's cytosolic part, triggering diverse cellular responses. These receptors become docking sites for SH2 (Src homology-2) or PTB (phosphotyrosine binding) domains of adaptor proteins, leading to the formation of signaling complexes and a cascade of phosphorylation events. Notably, the well-understood pathways include the RAS/MAP kinase, PI3 kinase/AKT, and PLCγ pathways.
Fig. 1 FGF signal pathway (Yun Y. R., et al. 2010).
RAS/MAP Kinase Pathway
The RAS/MAP Kinase Pathway is a central component of FGF signaling, regulating cellular activities such as gene expression, mitosis, differentiation, and survival. Upon FGF stimulation, phosphorylation of tyrosine residues on fibroblast growth factor receptor substrate 2α (FRS2α) initiates a signaling complex involving GRB2, SOS, SHP2, and GAB1. This leads to the activation of the RAS/MAP kinase and PI3 kinase/AKT pathways. The RAS/MAP kinase pathway's key role in cell growth and differentiation is well-established. Negative feedback loops, involving MAP kinase-mediated threonine phosphorylation of FRS2α, and inhibitory signals from proteins like sprouty, Sef, and MAP kinase phosphatases, modulate and fine-tune FGF signaling. XFLRT3, a leucine-rich-repeat transmembrane protein, acts as a novel positive modulator in the pathway. FGF signaling's nuanced regulation by positive and negative mechanisms plays a crucial role in determining biological responses during development.
PI3 Kinase/AKT Pathway
The PI3 Kinase/AKT Pathway, like the RAS/MAP kinase pathway, is initiated through the FRS2 signaling complex. Activated FGF receptors link with PI3 kinase via GAB1. GAB1, containing a pleckstrin homology domain, proline-rich region, and tyrosine phosphorylation sites, binds to p85, the adaptor protein's SH2 domains. This leads to the activation of phosphoinositide-dependent kinase and anti-apoptotic protein kinase AKT downstream. Implicated in cell survival, fate determination, and cell polarity control, the PI3 kinase/AKT pathway's role is crucial.
PLCγ Pathway
Activated FGFR targets phospholipase C gamma (PLCγ), phosphorylating Tyr-766 and activating PLCγ. PLCγ hydrolyzes phosphatidylinositol, producing inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium release from the endoplasmic reticulum, elevating cytosolic calcium levels. DAG, combined with increased calcium, activates protein kinase C (PKC). While its disruption doesn't abolish mitogenesis or cell differentiation, the pathway may be necessary for adhesion in some cell types.
References
- Ornitz D M.; Itoh N. Fibroblast growth factors. Genome Biology. 2001, 2(3): 1-12.
- Yun Y. R.; et al. Fibroblast growth factors: biology, function, and application for tissue regeneration. Journal of Tissue Engineering. 2010, 1(1): 218142.
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