The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). FGF signaling generally follows one of three transduction pathways: Ras/MAP kinase, PI3/AKT, or PLCγ. Each pathway likely regulates specific cellular behaviors. FGFs bind to their cognate receptors and activate c-Raf-1/ ERK1 (MAPK3)/ ERK2 (MAPK1) and Rac1/ p38 MAPK cascades, both of them are involved in the regulation of cell proliferation and differentiation. Activation of PI3K/AKT(PKB) promotes cell survival and epithelial-to-mesenchymal transition. PLCγ/ PKCs cascade takes part in the regulation of development and stress response in different tissues. Inappropriate expression of FGF and improper activation of FGFRs are associated with various pathologic conditions, unregulated cell growth, and tumorigenesis.
FGF and FGFR Family
The Fibroblast Growth Factor (FGF) family is comprised of secreted signaling proteins (secreted FGFs) that signal to receptor tyrosine kinases and intracellular non-signaling proteins (intracellular FGFs (iFGFs)). Members of both branches of the FGF family are related by core sequence conservation and structure and are found in vertebrates and invertebrates. There are 18 mammalian fibroblast growth factors (FGF1–FGF10 and FGF16–FGF23) which are grouped into 6 subfamilies based on differences in sequence homology and phylogeny.
The mammalian fibroblast growth factor receptor family has 4 members, FGFR1, FGFR2, FGFR3, and FGFR4. The FGFRs consist of three extracellular immunoglobulin-type domains (D1-D3), a single-span trans-membrane domain and an intracellular split tyrosine kinase domain. A hallmark of FGFRs is the presence of an acidic, serine-rich sequence in the linker between D1 and D2, termed the acid box. The D2–D3 fragment of the FGFR ectodomain is necessary and sufficient for ligand binding and specificity, whereas the D1 domain and the acid box are proposed to have a role in receptor autoinhibition.
The FGF ligands carry out their diverse functions by binding and activating the FGFR family of tyrosine kinase receptors in an HSGAG-dependent manner. FGF–FGFR binding specificity is regulated both by primary sequence differences between the 18 FGFs and the 7 main FGFRs (FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, and FGFR4) and by temporal and spatial expression patterns of FGFs, FGFRs, and HSGAGs. The alternative splice isoforms of FGFRs are generally tissue-specific.
A functional FGF–FGFR unit consists of two 1:1:1 FGF–FGFR–HSGAG complexes juxtaposed in a symmetrical dimer. HSGAG facilitates FGF–FGFR dimerization by simultaneously binding both FGF and FGFR, thereby promoting and stabilizing protein-protein contacts between ligand and receptor both within the 1:1 FGF–FGFR complex and between the two complexes in the 2:2 FGF–FGFR dimer. In addition to facilitating FGF–FGFR binding, HSGAGs stabilize FGFs against degradation, act as a storage reservoir for ligand and determine the radius of ligand diffusion.
Intracellular Signal Transduction
FGF binding activates the FGFR tyrosine kinase by inducing receptor dimerization and trans-autophosphorylation of the kinase domain. The activated FGFR phosphorylates adaptor proteins for four major intracellular signaling pathways, RAS-MAPK, PI3K-AKT, PLCγ, and signal transducer and activator of transcription (STAT).
Activation of the RAS-MAPK and PI3K-AKT pathway is initiated by phosphorylation of FRS2α. Activated (phosphorylated) FRS2α binds the membrane anchored adaptor protein, growth factor receptor-bound 2 (GRB2) and the tyrosine phosphatase SHP2. GRB2 further activates the RAS-MAPK pathway through recruitment of SOS, and the PI3K-AKT pathway through recruitment of GAB1 to the signaling complex. Phosphorylation of PLCγ by the activated FGFR tyrosine kinase leads to the hydrolysis of phosphatidylinositol 4,5-bisphosphate to produce inositol triphosphate (IP3) and diacylglycerol (DAG). The activated FGFR also phosphorylates and activates STAT1, STAT3, and STAT5, to regulate STAT pathway target gene expression.
FGF Family Signaling Pathway and Disease
The FGF signaling pathway plays many diverse and essential roles in orchestrating human embryonic development. Numerous studies have demonstrated that FGF signaling is a widely utilized regulatory system in early vertebrate development and has been conserved throughout chordate evolution. FGFs control cell migration during gastrulation, epithelio-mesenchymal interactions during limb morphogenesis, and neural induction and patterning in later stages of development. Besides, FGF signaling plays a critical role in the normal development and morphogenesis of the craniofacial skeleton during embryogenesis and postnatal growth.
Deregulated FGF signaling can contribute to pathological conditions either through gain- or loss-of-function mutations in the ligands themselves or through gain- or loss-of-function mutations in FGFRs, which contribute to many skeletal syndromes, Kallmann syndrome, LADD syndrome, and cancer.
Recently, significant research has focused on the therapeutic potential of FGF-FGFR signaling. To date, the therapeutic potential of FGFRs mostly relate to their role in tumorigenesis and cancer development. In particular, direct inhibition of FGFRs may improve outcomes of various cancers. The interference of the interaction of FGFR and its downstream signaling pathways has become a conceivable therapeutic strategy.