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WIREs Dev Biol
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The Fibroblast Growth Factor signaling pathway

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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). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS‐MAPK, PI3K‐AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non‐signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. WIREs Dev Biol 2015, 4:215–266. doi: 10.1002/wdev.176 This article is categorized under: Early Embryonic Development > Development to the Basic Body Plan Nervous System Development > Vertebrates: General Principles Birth Defects > Organ Anomalies
Mechanisms of FGF signaling during organogenesis. (a–c) Limb bud development uses a classical reciprocal epithelial‐mesenchymal FGF signal. The earliest identified event in limb bud development involves an FGF10 signal to coelomic epithelium (a). This induces an epithelial to mesenchymal transition (orange arrow) that increases the amount of mesenchyme (orange hash) at the forming limb bud, resulting in a bulge. As development progresses (b), FGF10 signals to ectoderm to induce the formation of the apical ectodermal ridge (AER). Initially FGF8 (blue hash) is expressed throughout its length of the AER (b) and later FGF4, FGF9, and FGF17 are also expressed in the posterior half of the AER. AER FGFs signal to FGFR1 and FGFR2 in distal mesenchyme. (d, e) Lung development uses a modified reciprocal mesothelial/epithelial‐mesenchymal FGF signal. The lung bud is initiated with an FGF10 signal from foregut mesenchyme to FGFR2b in foregut epithelium. Continued FGF10 expression is required for epithelial branching. Reciprocal signals from mesothelial FGF9 regulates mesenchymal proliferation through FGFR1 and FGFR2, while epithelial FGF9 functions as an autocrine factor to regulate epithelial branching through an as yet unidentified receptor. (f–h) Induction of the otic placode and differentiation of the otic vesicle. (f, g) FGF3, derived from the hindbrain and FGF10 derived from head mesenchyme, together, induce formation of the otic placode and its progression to the otic cup and otic vesicle. (h) After formation of the otic vesicle, FGF20 signals to FGFR1 within the prosensory epithelium (white hash) as a permissive autocrine factor required for differentiation of outer hair cells and outer supporting cells in the organ of Corti.
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FGF signaling pathways. (a) Binding of canonical FGFs to FGFR with HS (or HSPG) as a cofactor induces the formation of ternary FGF‐FGFR‐HS complex, which activates the FGFR intracellular tyrosine kinase domain by phosphorylation of specific tyrosine residues. The activated receptor is coupled to intracellular signaling pathways including the RAS‐MAPK, PI3K‐AKT, PLCγ, and STAT pathways. The RAS‐MAPK pathway: The major FGFR kinase substrate, FRS2α, which is constitutively associated with the juxtamembrane region of FGFR (peptide: MAVHKLAKSIPLRRQVTVSADS), interacts with CRKL bound to pY463 and is phosphorylated by the activated FGFR kinase. Phosphorylated FRS2α recruits the adaptor protein GRB2, which then recruits the guanine nucleotide exchange factor SOS. The recruited SOS activates the RAS GTPase, which then activates the MAPK pathway. MAPK activates members of the Ets transcription factor family such as Etv4 (Pea3) and Etv5 (Erm) and negative regulators of the FGF signaling pathways such as SHP2, CBL, SPRY, SEF, and DUSP6. The PI3‐AKT pathway: The recruited GRB2 also recruits the adaptor protein GAB1, which then activates the enzyme PI3K, which then phosphorylates the enzyme AKT. AKT has multiple activities including activation of the mTOR complex 1 through inhibition of TSC2 and phosphorylation of the FOXO1 transcription factor causing it to exit the nucleus. The PLCγ pathway: Activated FGFR kinase recruits and activates the enzyme PLCγ, which produces IP3 and DAG by the hydrolysis of PIP2. IP3 induces calcium ion release from intracellular stores and the activation of downstream signaling pathways. DAG activates the enzyme PKC and its downstream signaling pathways. GRB14 inhibits activation of PLCγ. The STAT pathway: FGFR kinase also activates STAT1, 3, and 5. STAT3 interacts with phosphorylated tyrosine 677 (pYxxQ motif). These activated signaling pathways mostly regulate gene expression in the nucleus. SPRY interacts with GRB2 to inhibit the RAS‐MAPK pathway and to regulate the PI3K‐AKT pathway. GRB2 dimers are docked at the c‐terminus of FGFR2 where they inhibit SHP2, allowing low‐level receptor kinase activity. Molecules shaded red generally function to inhibit FGFR signaling. (b) Dimerization of the FGFR1 kinase domain leads to sequential phosphorylation of tyrosine residues (1P–6P) leading to increasing activity of the FGFR kinase and phosphorylation of tyrosine substrates for CRKL, STAT, GRB14, and PLCγ binding. In the first phase of activation, Y653 (1P), in the activation loop, is phosphorylated, resulting in a 50‐ to 100‐fold increase in kinase activity. In the third phase of activation, Y654 (6P), in the activation loop, is phosphorylated, resulting in an overall 500–1000 fold increase in kinase activity. Y730 is weakly phosphorylated. Phosphorylation of Y677 allows docking of STAT3 and phosphorylation of Y766 allows docking of either GRB14 or PLCγ. Ligand‐induced receptor activation phosphorylates GRB2, leading to its dissociation from the receptor. Tyrosine residues correspond to human FGFR1 (accession NP_075598). (c) Binding of endocrine FGF to FGFR with Klotho as a cofactor induces the formation of ternary FGF‐FGFR‐Klotho complex, which leads to activation of the FGFR tyrosine kinase. (d) FGFRL1 is a protein containing three extracellular immunoglobulin‐like domains with similarity to FGFRs. FGFRL1 has a single transmembrane domain, and a short intracellular tail with no tyrosine kinase domain. The short cytoplasmic domain contains an SH2 binding motif that interacts with SHP1. FGFRL1 is not simply a decoy receptor, but rather a non‐tyrosine kinase signaling molecule.
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Receptor specificity of canonical and endocrine FGFs. The six subfamilies of signaling FGFs use either heparin‐like molecules or Klotho molecules as cofactors for receptor binding. Data is derived from receptor activation assays using BaF3 cells, L6 myoblasts, or HEK293 cells transfected with individual splice variants of FGFRs or by direct binding studies. FGFR4Δ is a two immunoglobulin‐like domain form of FGFR4.
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FGF and FGFR families. (a) Phylogenetic analysis suggests that 22 Fgf genes can be arranged into seven subfamilies containing two to four members each. Branch lengths are proportional to the evolutionary distance between each gene. The Fgf1, Fgf4, Fgf7, Fgf8, and Fgf9 subfamily genes encode secreted canonical FGFs, which bind to and activate FGFRs with heparin/HS as a cofactor. The Fgf15/19 subfamily members encode endocrine FGFs, which bind to and activate FGFRs with the Klotho family protein as a cofactor. The Fgf11 subfamily genes encode intracellular FGFs, which are non‐signaling proteins serving as cofactors for voltage gated sodium channels and other molecules. (b) Schematic representations of FGFR protein structures are shown. FGFR is a receptor tyrosine kinase of ∼800 amino acids with several domains including three extracellular immunoglobulin‐like domains (I, II, and III), a transmembrane domain (TM), and two intracellular tyrosine kinase domains (TK1 and TK2). SP indicates a cleavable secreted signal sequence. The Fgfr gene family is comprised of four members, Fgfr1‐Fgfr4. Among them, Fgfr1–Fgfr3 generate two major splice variants of immunoglobulin‐like domain III, referred to as IIIb and IIIc, which are essential determinants of ligand‐binding specificity. (c) The schematic representation of FGFRL1/FGFR5 protein structure is shown. FGFRL1, with structural similarity to FGFRs, is a membrane protein of ∼500 amino acids with three extracellular immunoglobulin‐like domains (I, II, and III), a transmembrane domain (TM), and a short intracellular tail with no tyrosine kinase domain. SP indicates a cleavable secreted signal sequence.
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Activating mutations in FGFRs in heritable and acquired disease. (a) Wild type FGFR‐FGF‐HS complex. (b) Missense mutations in the linker between immunoglobulin‐like domain II and III affect the affinity and specificity of the receptor. The Apert syndrome mutation, S252W, allows FGF10 to activate the IIIc splice variant of FGFR2. (c) Missense mutations in the transmembrane domain, as seen in the G380R Achondroplasia mutation, weakly activates the receptor in a ligand dependent manner by impeding receptor internalization. (d) The strongly activating ligand independent mutation, R248C, in Thanatophoric dysplasia, type I, causes constitutively active disulfide linked receptor dimers. (e) Mutations in the tyrosine kinase domain, as seen in the K640E Thanatophoric dysplasia, type II mutation, are often ligand independent and result in receptor autophosphorylation and signaling from intracellular sites such as the endoplasmic reticulum.
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