The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.
Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.
This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.
View original pathway at Reactome.
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Gerber SD, Amann R, Wyder S, Trueb B.; ''Comparison of the gene expression profiles from normal and Fgfrl1 deficient mouse kidneys reveals downstream targets of Fgfrl1 signaling.''; PubMedEurope PMCScholia
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Mohammadi M, Honegger AM, Rotin D, Fischer R, Bellot F, Li W, Dionne CA, Jaye M, Rubinstein M, Schlessinger J.; ''A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1.''; PubMedEurope PMCScholia
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While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
The phospho-tyrosine positions for FRS2-beta were inferred by similarity to the analogous positions in FRS2-alpha. Five out of six tyrosine positions in alpha are present in beta.
While the existence of a "b" isoform of fibroblast growth factor receptor 1 is well established and its biochemical and functional properties have been extensively characterized (e.g., Mohammadi et al. 2005; Zhang et al. 2006), its amino acid sequence is not represented in reference protein sequence databases, except as the 47-residue polypeptide (deposited in GenBank as accession AAB19502) first used by Johnson et al. (1991) to distinguish the "b" and "c" isoforms of the receptor.
SPRY2 translocates to the plasma membrane upon activation of cells with FGF, and translocation is required for the inhibition of growth factor-stimulated cell migration, proliferation and differentiation. Translocation may be mediated by interactions with PIP2 in the membrane, palmitoylation of the C-terminal region of SPRY2 and/or interactions with caveolin-1.
Sprouty 2 protein is phosphorylated on tyrosine residue 55. The ability of SRC kinase to catalyze this reaction has been demonstrated with purified proteins in vitro (Li et al. 2004) and in cultured cells with studies of the effects of SRC-family pharmacological inhibitors and of dominant-negative mutant SRC proteins (Mason et al. 2004). SRC kinase also phosphorylates numerous tyrosine residues in the C terminal region of SPRY2 including Y227, in response to FGF but not EGF stimulation.
Some evidence suggests that SPRY2 may exert its negative effect by binding to GRB2 and competing with the GRB2:SOS1 interaction that is required for MAPK activation. SPRY2 phosphorylation at Y55 is stimulated in response to both FGF and EGF, and is required for SPRY2 to act as a negative regulator of FGF signaling. Y55 is not thought to be a GRB2 binding site, however. Instead, phosphorylation at Y55 is thought to cause a conformational change in SPRY2 that reveals a cryptic PXXPXPR GRB2-docking site in the C-terminal of SPRY2. SPRY2 has also been shown to be phosphorylated at multiple tyrosine residues in its C-terminal in response to FGF, but not EGF, stimulation. This phosphorylation, in particular at residue 227, is thought to augment the ability of SPRY2 to inhibit FGF signaling through the MAPK cascade, although the mechanism remains to be elucidated.
The N terminal TKB domain of CBL binds to the phospho-tyrosine 55 of SPRY2, targeting SPRY2 for degradation by the 26S proteasome. Y55 is also a binding site for PP2A, which dephosphorylates numerous serine and threonine residues on SPRY2, allowing a conformational change that may promote a SPRY2:GRB2 interaction and limit the extent of MAPK activation following FGF stimulation.
In unstimulated cells, SPRY2 has been shown to be phosphorylated on multiple serine and threonine residues. In these cells, SPRY2 exists in a complex with the regulatory and catalytic subunits (A and C, respectively) of the serine/threonine phosphatase PP2A. After stimulation with FGF, the catalytic activity of PP2A increases and the phosphatase dephophorylates SPRY at serine 112 and serine 115. This is thought to promote changes in tertiary structure that promote GRB2 binding and phosphorylation of Y55 and Y227.
Some evidence suggests that SPRY2 can exert its negative role on FGF signaling at the level of RAF activation. Hypophosphorylated SPRY2 binds to inactive B-RAF, preventing it from activating ERK signaling. MAPK activation results in phosphorylation of SPRY2 on six serine residues (S7, S42, S111, S120, S140 and S167), and inhibits B-RAF binding. Phosphorylation at S111 and S120 directly affects B-RAF binding while the remaining four sites appear to contribute indirectly. Oncogenic forms of B-RAF such as B-RAF V600E, which adopt active kinase conformations, do not associate with SPRY2, regardless of its phosphorylation status. This suggests that two mechanisms affect the SPRY2:B-RAF interaction: SPRY2 phosphorylation and B-RAF conformation.
PPTN11 (also known as SHP2) may exert its positive effects on MAPK activation in response to FGF stimulation by catalyzing the dephosphorylation of tyrosine resides on SPRY2. This dephosphorylation promotes dissociation of the GRB2/SPRY2 complex and as a consequence stimulates GRB2 association with the activated receptor, leading to sustained MAPK signaling.
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1.
8p11 myeloproliferative syndrome (EMS) is a myeloproliferative disorder that rapidly progresses to acute myeloid leukemia if not treated (reviewed in Jackson, 2010, Knights and Cook, 2010). A characteristic feature of EMS is the presence of fusion proteins that contain the kinase domain of FGFR1 and the oligomerization domain of an unrelated protein. This is believed to promote the ligand independent dimerization and activation of the kinase domain. To date, there are 11 identified partners that form fusion proteins with FGFR1 in EMS: ZMYM2 (Xiao, 1998; Popovici, 1998; Reiter, 1998; Ollendorff, 1999; Xiao, 2000), FGFR1OP1 (Popovici, 1999), CNTRL (Guasch, 2000), BCR (Demiroglu, 2001), FGFR1OP2 (Grand, 2004), TRIM24 (Belloni, 2005), CUX1 (Wasag, 2011), MYO18A (Walz, 2005), CPSF6 (Hidalgo-Curtis, 2008), HERV-K (Guasch, 2003) and LRRFIP1 (Soler, 2009).
In a murine mouse model of ZNF198-FGFR1-induced EMS, treatment with the FGFR-inhibitor Midostaurin (PKC412) resulted in prolonged survival (Chen, 2004). Similarly, growth of ZNF-198-FGFR1-, FGFR1OP2-FGFR1-, and BCR-FGFR1-expressing lines is blocked by treatment with FGFR-inhibitors (Demiroglu, 2001; Gu, 2006; Chase, 2007; Zhen, 2007; Wasag, 2011).
After ligand-independent dimerization, FGFR1 fusions are trans-autophosphorylated on tyrosine residues (see for instance Popovici, 1998; Ollendorff, 1999; Guasch, 2000). Although the sites of tyrosine phosphorylation have not been mapped in the context of the fusion proteins, at least some of the same residues appear to be phosphorylated as in full length FGFR1. For instance, phospho-specific antibodies have demonstrated that TRIM24 is phosphorylated on Y653 and Y654, the activation loop tyrosines of FGFR1 (Belloni, 2005). Likewise, FGFR1 fusions with ZMYM2, BCR, FGFR1OP and TRIM24 all result in recruitment and phosphorylation of PLCgamma, and where mutational studies have been performed, mutation of the PLCgamma binding site Y766 has been shown to abrogate this signaling (Roumiantsev, 2004, Lelievre, 2008, Chase, 2007). In the case of BCR-FGFR1, the BCR moiety of the fusion protein has also been shown to be phosphorylated on at least one tyrosine residue, Y177, which results in the recruitment of GRB2 (Roumiantsev, 2004).
Unique among FGFR1 fusion proteins, which generally give rise to an atypical myeloproliferative syndrome (EMS) (reviewed in Jackson, 2010), the BCR-FGFR1 fusion results in a more typical chronic myeloid leukemia (CML). Although both EMS and CML activate PLCgamma signaling, and mutation of the FGFR1 Y766 PLCgamma binding site attenuates both diseases, CML-specific signaling also appears to be mediated through the BCR portion of the fusion protein. BCR Y177 binds GRB2-GAB1 and induces CML-like leukemia in mice, while expression of a Y177F BCR-FGFR1 fusion induces EMS-like disease (Roumiantsev, 2004).
Activation of the PI3K signaling pathway has been demonstrated for a number of FGFR1 fusion proteins and inhibitors of this pathway impair the proliferative and survival function of the fusions (Guasch, 2001; Demiroglu, 2001; Chen, 2004; Lelievre, 2008). FGFR1 fusions lack the FRS2-binding site of the full length protein, so the mechanism of PI3K recruitment is unclear. Unlike BCR-FGFR1, which has been shown to recruit GRB2 through the BCR Y177 site, GRB2 did not co-precipitate with the ZMYM2-FGFR1 fusion (Roumianetsev, 2004). In the case of FOP-FGFR1, Y730 has been shown to be required for the recruitment of the p85 subunit of PI3K; however, CEP110-FGFR1, which contains Y730 in the context of the same pYXXM motif, was not shown to recruit p85 at the centrosome (Guasch, 2001).
Activation of the PI3K pathway has been demonstrated in the case of ZMYM2-FGFR1 (Chen, 2004), BCR-FGFR1 (Demiroglu, 2001) and FOP-FGFR1 (Guasch, 2001), and is presumed to occur to a greater or lesser extent in other FGFR1 fusions as well (reviewed in Jackson, 2010). Activation of the PI3K pathway suggests that the PIK3CA catalytic subunit must be recruited to the fusion protein.
Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007).
Although it has not been rigourously established, there is some evidence that PLC-gamma signaling may be activated after autophosphorylation of some FGFR mutants, analagous to the wild type receptor (see for instance, Hart, 2000; Chen, 2005; Cha, 2008; di Martino, 2009; Gartside, 2009; Cross, 2000; Hatch, 2006). The extent to which each of the mutants activates this pathway and to which proliferation and tumorigenesis relies on PLC-gamma dependent signaling, remains to be more firmly established. FGFR1 fusions with ZMYM2, BCR, FGFR1OP and TRIM24 all result in recruitment and phosphorylation of PLCgamma, and where mutational studies have been performed, mutation of the PLCgamma binding site Y766 has been shown to abrogate this signaling (Guasch, 2001; Roumiantsev, 2004, Lelievre, 2008, Chase, 2007). In the case of BCR-FGFR1 and ZMYM2-FGFR1, mutation of the PLCgamma binding site significantly decreased the transformative phenotype of the FGFR1 fusion (Roumiantsev, 2004).
Proliferation of BCR-FGFR1 fusion proteins is blocked by treatment with the PI3K inhibitor LY294002, suggesting the activation of this pathway downstream of BCR-FGFR1 phosphorylation. Y177 has been shown to be a binding site for GRB2 and to be required for the both the phosphorylation of GAB2 and the development of CML-like disease (Roumiantsev, 2004, Demiroglu, 2001). By analogy with studies in BCR-ABL, where mutation of Y177 abrogates recruitment of PI3K activity to the fusion protein (Sattler, 2002), this suggests that Y177 may serve as a docking site for a complex of GRB2:GAB1:PI3K in the context of BCR-FGFR1 as well.
By analogy with the wild-type pathway, PLC-gamma is presumed to be phosphorylated by activated FGFR mutants, resulting in PLC-gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3.
Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate.
Activation of the PI3K pathway has been demonstrated in the case of ZMYM2-FGFR1 (Chen, 2004), BCR-FGFR1 (Demiroglu, 2001) and FOP-FGFR1 (Guasch, 2001), and is presumed to occur to a greater or lesser extent in other FGFR1 fusions as well (reviewed in Jackson, 2010). Activation of the PI3K pathway suggests that the PIK3CA catalytic subunit must be recruited to the fusion protein.
Once recruited to the activated BCR-FGFR1 fusion PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling (Roumiantsev, 2004; Demiroglu, 2001).
Recruitment of GAB2 to the BCR-FGFR1 fusion protein results in GAB2 phosphorylation (Roumiatnetsev, 2004). As in the case of BCR-ABL (Sattler, 2002), recruitment and phosphorylation of GAB2 is dependent on BCR residue Y177. Deletion of Y177 abolishes GRB2 recruitment and converts the more aggressive MPD disorder induced by BCR-FGFR1 to the EMS characteristic of other FGFR1 fusions (Demiroglu, 2001; Roumianetsev, 2004)
Activation of a subset of FGFR1-fusions (ZMYM2, BCR, FGFR1OP2 and CUX) has been shown to result in downstream phosphorylation of STAT5 proteins at Y694. This phosphorylation is dependent on the FGFR1 fusion, as the STAT5 phosphorylation is abrogated in the presence of an FGFR1-kinase dead fusion (Heath and Cross, 2004; Smedley, 1999; Chase, 2007; Wasage, 2011).
Based on analogy with studies of the BCR-ABL fusion, phosphorylated GAB2 recruits the regulatory subunit of PI3K to the BCR-FGFR1 fusion (Sattler, 2002; Demiroglu, 2001; Roumiantsev, 2004).
Expression of FGFR1OP-FGFR1 in both Ba/F3 and Cos-1 cells leads to phosphorylation of STAT1 and STAT3 but not STAT5, and to activation of a STAT1/3-responsive reporter when expressed in NIH3T3 cells (Guasch, 2001). Activation of STAT proteins has also been shown to be oncogenic in the context of derivatives of FGFR1, 3 and 4 that lack the extracellular domain and are are targetted to the plasma membrane by a myristylation signal (Hart et al, 2000).
In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. NCAM and other members of the CAM protein family directly or indirectly modulate this interaction in a variety of neural tissues. The details of this interaction in vivo have not been definitively established at the molecular level, but are thought to play a central role in the regulation of the development of these tissues.
In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate.
In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate.
Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators.
Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators.
Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators.
FGFR1-amplified lung cancer and breast cancer cells show strong phosphorylation of FGFR1 and do not show elevated levels of FGF ligand, suggesting that these receptors can undergo ligand-independent activation. Phosphorylation is enhanced in the presence of exogenous ligand, supporting the notion that overexpressed FGFR1 can be activated by both ligand- and ligand-independent pathways (Koziczak, 2004; Dutt, 2008; Weiss, 2010). The biochemical consequences of overexpression of FGFR1 in other cancer types remain to be determined (reviewed in Turner and Gross, 2010; Wesche, 2011.
FGFR1-amplified lung cancer and breast cancer cells show strong phosphorylation of FGFR1 and do not show elevated levels of FGF ligand, suggesting that these receptors can undergo ligand-independent activation. Phosphorylation is enhanced in the presence of exogenous ligand, supporting the notion that overexpressed FGFR1 can be activated by both ligand- and ligand-independent pathways (Koziczak, 2004; Dutt, 2008; Weiss, 2010). The biochemical consequences of overexpression of FGFR1 in other cancer types remain to be determined (reviewed in Turner and Gross, 2010; Wesche, 2011.
The missense mutation C775G in exon 5 of FGFR1 encodes a Pro252R gain-of-function mutation that causes Pfeiffer syndrome, an autosomal dominant disorder characterized by premature fusion of bones in the skull and syndactyly of the hands and feet (Muenke, 1994). FGFR1 P252R binds to FGF1, FGF2, FGF4, and FGF6 with 2-5 fold-enhanced affinity, and with 30-fold affinity to FGF9. The enhanced ligand-affinity of the mutant receptor is the result of an additional set of ligand-receptor hydrogen bonds; in particular for FGF9, the additional receptor contacts are thought to compete with FGF9 autoinhibitory dimerization (Ibrahimi, 2004a). The increase in ligand-binding affinity in the absence of an expansion of ligand binding range is thought to account for the milder limb phenotype of Pfeiffer syndrome relative to FGFR2-mediated Apert syndrome (Yu, 2000; Ibrahimi, 2004b).
Somatic mutations in FGFR1 at P252 have also been identified in melanoma (P252S; Ruhe, 2007) and in lung cancer (P252T; Davies, 2005). Based on analogy to the FGFR1 P252R mutation that is found in Pfeiffer syndrome, these mutations are also predicted to increase the ligand-binding affinity of the receptor and to result in increased signaling, although this remains to be directly demonstrated for the S/T alleles (Ibrahimi, 2004a).
FGFR1 gain-of-function mutations at P252 that result in increased binding affinity to ligand are presumed to be phosphorylated on the same sites as the wild-type receptor, although this has not been demonstrated (Ibrahimi, 2004a).
Large scale genomic characterization of glioblastoma tumors has identified three point mutants in the kinase domain of FGFR1: N546K, R576W and K656E (Rand, 2005, TCGA, 2008), representing the first kinase domain point mutants identified in this gene in any cancer. These mutants are believed or have been shown to have enhanced kinase activity and to be able to function in a ligand-independent manner (Petiot, 2002; Lew, 2009; Raffioni, 1998, Rand, 2005; Hart, 2000)
The three kinase domain mutants of FGFR1 that have been identified in glioblastoma are predicted or have been shown to result in enhanced kinase activity. The N546K (Rand, 2005) residue lies in a stretch of 9 amino acids that are conserved between all four FGFRs. Mutation of the paralogous residue in FGFR3 (N540K) has been shown to result in weak ligand-independent contstitutive activation in the autosomal disorder hypochodroplasia (Raffioni, 1998). In FGFR2 mutation of the paralogous residue to lysine has been identified in endometrial cancer and been shown to result in enhanced kinase activity (Dutt, 2008; Pollock, 2008); germline mutations at this site in FGFR2 are also associated with the development of Crouzon and Pfeiffer syndromes (Kan, 2002). The FGFR1 N546K mutations has accelerated rates of autophosphorylation and supports transformation when transfected into Rat-1 cells (Lew, 2009).
The FGFR1 K656E (TCGA, 2008) mutation is paralogous to activating mutations in FGFR3 kinase domain associated with the development of thanatophoric dysplasias (Tavormina, 1999; Bellus, 2000; Hart, 2000), and has itself been shown to activating when expressed in neural crest cells (Petiot, 2002).
The FGFR1 R576W (Rand, 2005) mutation increases the hydrophobicity of the receptor, and is postulated to enhance protein-protein interactions and thereby increase the likelihood of autophosphorylation of adjacent tyrosine residues, although this has not been explicitly demonstrated.
Treatment of FGFR1-amplified lung and breast cancer cell lines with the in vitro reagents PD173704, SU5402 and FIIN-1 inhibits proliferation, while cells expressing wild-type levels of FGFR1 are insensitive to inhibitors, suggesting that amplified FGFR1 may be a suitable therapeutic target in some cancer lines (Weiss, 2010; Reis-Filho, 2006; Dutt, 2011; Turner, 2010). In fact, a number of other small molecule inhibitors, including Dovitinib and AZD4547, are currently in clinical trials for treatment of FGFR1-amplified cancers (reviewed in Turner and Grose, 2010; Wesche, 2011; http://ClinicalTrials.gov)
PLC gamma is phosphorylated by activated FGFR, resulting in PLC gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. Tyrosine phosphorylation of PLCgamma by FGFR4 is weaker than that seen by other isoforms of FGFR.
Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate.
Recruitment of PLC-gamma by FGF receptors has been best studied in FGFR1c signaling, where it has been shown that autophosphorylation of Tyr766 in the C-terminal tail of FGFR1c creates a specific binding site for the SH2 domain of PLC-gamma. A mutant FGFR1c in which Y766 is replaced by phenylalanine is unable to activate PI hydrolysis and Ca2+ release in response to FGF stimulation. Membrane recruitment of PLC-gamma is also aided by binding of the Pleckstrin homology (PH) domain of this enzyme to PtIns(3,4,5) P3 molecules that are generated in response to PI-3 kinase stimulation. By sequence comparison, Y766 is conserved in all FGFR isoforms, and PLC-gamma signaling is observed, to a greater or lesser extent, downstream of all FGFR receptors upon stimulation with FGFs.
FGFRL1 binds to SPRED1 and 2 and Sprouty1 as assessed by co-immunoprecipitation, although the exact stoichiometry of the complex remains to be determined. The interaction requires the C-terminal residues of the short intracellular domain of FGFRL1 (Zhuang et al, 2011). The SPRED proteins are members of the Sprouty family, with established roles as negative regulators of the Ras/Raf/Erk signaling pathway (reviewed in McClatchey and Cichowski, 2012).
FGFRL1 is a fifth member of the FGFR family of receptors that shares 40% sequence similarity with the extracellular region of FGFR1-4, but FGFRL1 lacks the internal kinase domain required for typical downstream FGFR signaling. Instead, FGFRL1 has a short intracellular domain with a C-terminal histidine rich region that has been shown to interact with the MAP kinase regulator SPRED proteins (Sleeman et al, 2001; Zhuang et al, 2011; reviewed in Trueb et al, 2013). FGFRL1 forms constitutive dimers and has been shown to bind to a wide range of FGF ligands, including FGF3,4,8,10, 22 and with lower affinity to FGF2,5,17,18 and 23 (Reickman et al, 2008; Steinberg et al, 2010). FGFRL1 knockout mice die shortly after birth from lung and renal defects (Gerber et al, 2009; Gerber et al, 2012; Trueb et al, 2013). FGFRL1 has been postulated to act as a decoy receptor that sequesters ligand away from canonical FGF receptors; more recently, however, alternate roles for FGFRL1 in enhancing ERK1/2 activation or promoting FGFR1-mediated signaling have been suggested (Sleeman et al, 2001; Steinberg et al, 2010; Silva et al, 2013; Amann and Trueb, 2013). Further work will be required to elucidate the role(s) of FGFRL1.
KAL1 is an extracellular matrix-associated protein that modulates signaling by FGFR1c. Mutations in the KAL1 gene are associated with Kallman syndrome, a genetic disorder characterized by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism (Dode et al, 2003; Pitteloud et al, 2006; reviewed in Hu and Bouloux, 2010). KAL1 has been shown to interact with both FGFR1c and with heparan sulfate, with opposing effects on downstream signaling. Preformation of an FGFR1c:KAL1 complex inhibits the association of FGF ligand with the complex and subsequent receptor dimerization and in this way negatively regulates FGFR1c ligand-dependent signaling. In contrast, preformation of a KAL1:heparan sulfate complex promotes stable FGF ligand:receptor interaction thereby enhancing FGFR1c signal transduction (Hu et al, 2009; Hu et al, 2004; Soussi-Yanicostas et al, 1998). KAL1 consists of an N-terminal cysteine rich domain, a whey acidic protein-like (WAP) domain, four fibronectin III (FnIII) repeats and a C-terminal histidine rich region. The N-terminal cysteine rich region, the WAP domain and the first FnIII domain contribute to the interaction with the D2 and D3 Ig-like domains of FGFR1c. D1 and the acid box of the receptor inhibit the interaction with KAL1 in a manner analogous to the inhibition of FGF binding (Hu et al, 2009). Consistent with this, missense mutations in D1 and the acid box that affect the interaction with KAL1 have been identified in patients with Kallmann syndrome (Dode and Hardelin, 2009). Similarly, loss-of function mutations in the FnIII domain of KAL1 that disrupt the interaction with FGFR1c have also been characterized (Hu et al, 2009; Robertson et al, 2001; Gonzalez-Martinez et al 2004; Oliviera et al, 2001).
KAL1 is an extracellular matrix-associated protein that modulates signaling by FGFR1c. Mutations in the KAL1 gene are associated with Kallmann syndrome, a genetic disorder characterized by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism (Dode et al, 2003; Pitteloud et al, 2006; reviewed in Yu and Bouloux, 2010). KAL1 has been shown to interact with both FGFR1c and with heparan sulfate, with opposing effects on downstream signaling. Preformation of an FGFR1c:KAL1 complex inhibits the association of FGF ligand with the complex and subsequent receptor dimerization and in this way negatively regulates FGFR1c ligand-dependent signaling. In contrast, preformation of a KAL1:heparan sulfate complex promotes stable FGF ligand:receptor interaction thereby enhancing FGFR1c signal transduction (Hu et al, 2009; Hu et al, 2004; Soussi-Yanicostas et al, 1998).
FGFR1-amplified lung cancer and breast cancer cells show strong phosphorylation of FGFR1 and do not show elevated levels of FGF ligand, suggesting that these receptors can undergo ligand-independent activation. Phosphorylation is enhanced in the presence of exogenous ligand, supporting the notion that overexpressed FGFR1 can be activated by both ligand- and ligand-independent pathways (Koziczak, 2004; Dutt, 2008; Weiss, 2010). The biochemical consequences of overexpression of FGFR1 in other cancer types remain to be determined (reviewed in Turner and Gross, 2010; Wesche, 2011.
FGFR1-amplified lung cancer and breast cancer cells show strong phosphorylation of FGFR1 and do not show elevated levels of FGF ligand, suggesting that these receptors can undergo ligand-independent activation. Phosphorylation is enhanced in the presence of exogenous ligand, supporting the notion that overexpressed FGFR1 can be activated by both ligand- and ligand-independent pathways (Koziczak, 2004; Dutt, 2008; Weiss, 2010). The biochemical consequences of overexpression of FGFR1 in other cancer types remain to be determined (reviewed in Turner and Gross, 2010; Wesche, 2011.
FRS2 has 8 canonical MAPK phosphorylation sites which are phosphorylated by activated ERK1/2 after FGF stimulation. Phosphorylation of these 8 threonine residues counteracts the activating effect of tyrosine phosphorylation of FRS2, although the exact mechanism for this negative regulation is not known. Expression of a version of FRS2 in which the 8 threonine residues are mutated to valine results in enhanced tyrosine phosphorylation of FRS2, enhanced GRB2-SOS1 recruitment and a more sustained MAPK response. The 8 threonine residues are not conserved in FRS3; as a result, signaling through FRS3 complexes do not appear to be subject to this downregulation.
FRS2 (also known as FRS2alpha) is broadly expressed in adult and fetal tissues. Membrane-bound FRS2 interacts with FGFR as a first step in the phosphorylation of this docking protein. The juxtamembrane binding site for FRS2 does not contain tyrosine, so binding may be independent of receptor activation and/or constitutive. Activation of the FGFR receptor is required for FRS2 phosphorylation and subsequent recruitment of downstream effectors.
FRS3 (also known as FRS2beta) is predominantly expressed in the developing and adult neuroepithelium. As is the case for FRS2 (also known as FRS2alpha), binding of FRS3 to FGFR may be constitutive and/or independent of receptor activation. Elements of the downstream signaling mediated by the two FRS family members appear to be at least partially conserved, as FRS3 is phosphorylated upon FGF stimulation, binds PPTN11/SHP2 and GRB2 and results in ERK activation. Moreover, expression of FRS3 in FRS2-/- MEFs restores ERK activation.
FRS2 (also known as FRS alpha is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. FRS2 contains four binding sites for the adaptor protein GRB2 at residues Y196, Y306, Y349 and Y392, and two binding sites for the protein tyrosine phosphatase PPTN11/SHP2 at residues Y436 and Y471. Different FGFR isoforms may generate different phosphorylation patterns on FRS2 leading to alternate downstream signaling.
FRS3 (also known as FRS2 beta) is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. By sequence comparison, FRS3 has the 2 PPTN11/SHP2-binding sites and has three of the four GRB2-binding sites.
The p46 and p53 isoforms of SHC1 have been shown to be phosphorylated upon FGF stimulation. Three consensus RTK phosphoryation sites are present in SHC1, although phosphorylation of these specific tyrosine residues has not been explicitly demonstrated in response to FGF stimulation. In contrast, the p66 isoform of SHC1 does not appear to undergo FGF-dependent phosphorylation.
Tyrosine phosphorylated FRS2 recruits GRB2:SOS1 complex by means of the SH3 domain of GRB2, leading to RAS-MAP kinase activation. The FRS2:GRB2-mediated pathway plays a minor role in the activation of RAS-MAP kinase pathway compared to that mediated by FRS2:PPTN11.
Tyrosine phosphorylation of PPTN11/SHP2 by FGFR kinase is required for activation of the phosphatase activity of PPTN11 and for downstream signaling. Tyrosine phosphorylated PPTN11 plays a major role in the activation of RAS-MAP kinase pathway, although the precise role is not yet clear.
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011).
Phosphorylated SHC1 links FGFR to Grb2 (Klint et al. 1995) leading to the formation of a signaling complex including Shc, Grb2 and Sos. Transformation of NIH 3T3 cells with v-Src produced a strong constitutive association of FGFR1 with Shc, Grb2 and Sos (Curto et al. 1998) suggesting Src involvement. Recruitment of Grb2-Sos links FGFR to the Ras pathway.
Grb2 bound to tyrosine phosphorylated FRS2 forms a ternary complex with Cbl through the binding of the SH3 domains of Grb2 to a proline rich region in Cbl. Grb2-mediated recruitment of Cbl results in ubiquitination of FGFR and FRS2. Cbl is a multidomain protein that posses an intrinsic ubiquitin ligase activity and also functions as a platform for recruitment of a variety of signaling proteins. Multiple mechanisms appear to be required for downregulation of FGFR, as internalization of the receptor is reduced but not abolished if recruitment of CBL to FRS2 is compromised by mutation of GRB2-binding sites.
The ubiquitin ligase CBL exists in a complex with GRB2 and is recruited to tyrosine-phosphorylated FRS2 after FGF stimulation. In addition to promoting the ubiquitination, endocytosis, and degradation of the activated receptor complex, recruitment of the p-CBL:GRB2 complex seems to attenuate FGFR signaling by competing with GRB2:SOS1 for binding to the direct GRB2-binding sites on p-FRS2.
Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007).
The three fibronectin-leucine-rich transmembrane (FLRT) proteins were identified as positive regulators of FGFR signaling that enhance FGFR-dependent RAS/MAPK pathway activation. All three FLRT proteins have been shown to interact with FGFR1 by co-immunoprecipitation and, at least in the case of FLRT3, the interaction is mediated by the FLRT fibronectin-like domain (Bottcher et al, 2004; Haines et al, 2006). Each FLRT gene has a distinct expression pattern and the strength of the protein-protein interaction with the FGF receptor varies, allowing for cell-type specific modulation of signaling activity (Haines et al, 2006). How the FLRT proteins act to enhance FGFR-dependent MAPK pathway activation is not clear, however FLRT1 has recently been shown to be phosphorylated in an FGFR1- and Src family kinase (SFK)-dependent manner (Wheldon et al, 2010).
Although dimerization of the FGFR1 fusions in glioblastoma, breast cancer and non small cell lung cancer hasn't been directly demonstrated, the ability of these proteins to promote transformation and tumorigenesis suggests that they form active oligomers as is the case for WT FGFR1 proteins (Singh et al, 2012; Wang et al, 2013; Wang et al, 2014; reviewed in Parker et al, 2014).
Although it hasn't been directly demonstrated in all cases, the ability to promote transformation and anchorage independent growth suggests these fusions undergo autophosphorylation similar to WT FGFR1 proteins. Indeed, active kinase activity has been demonstrated for the the ERLIN2-FGFR1 fusion identified in breast cancer (Singh et al, 2012; Wu et al, 2013; Wang et al, 2014; reviewed in Parker et al, 2014)
RAS nucleotide is stimulated downstream of activated FGFR1 in a p-PTPN11-dependent manner. The phosphatase activity of PTPN11 is required for activation of the RAS-MAP kinase pathway, although the mechanism for RAS pathway activation is not yet clear (Hadari et al, 1998; reviewed in Mohi et al, 2007; Gotoh et al, 2008).
In humans, the phosphorylated MNK1 kinase phosphorylates the adaptor protein Sprouty2 on Ser112 and Ser121, and also at some other serine and threonine residues. MNK1 appears not to form a complex with Sprouty2. Some of these (including the two main sites mentioned above) conform to the serine-containing consensus sites for phosphorylation by MNK1 kinase (K/R-X-X-S, R-X-S). It appears that serine phosphorylation is required to protect Sprouty2 from degradation.
In the absence of serine phosphorylation, phosphorylation of Tyr55 and subsequent binding to E3 ubiquitin ligase, CBL, is enhanced. Serine phosphorylation of Sprouty2 appears to stabilise the protein by interfering with its potential phosphorylation of Tyr55 (Sprouty2 appears to be a poor substrate for c-Src kinase) in response to growth factor stimulation.
In humans, the phosphorylated adaptor protein Sprouty2 is ubiquitinated by the E3 ubiquitin ligase CBL, marking it for degradation by the 26S proteasome.
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overexpressed
FGFR1b homodimeroverexpressed
FGFR1c homodimermutant dimers with enhanced kinase
activitymutants and
fusion:p-PLCG1mutants and
fusions:PLCG1bound to
FGF23:Klothowith enhanced
kinase activityenhanced kinase
activitydimers bound to
FGFsdimer:SPRED1/2
dimer(A:C):S112/S115
p-SPRY2The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
inhibitors of
overexpressed FGFR1inhibitors of FGFR1
fusion mutantsfusion mutant
dimersfusion mutant
dimersfusion mutant
dimersmutant
dimers:PIK3R1Annotated Interactions
overexpressed
FGFR1b homodimeroverexpressed
FGFR1c homodimermutant dimers with enhanced kinase
activitymutants and
fusion:p-PLCG1mutants and
fusion:p-PLCG1mutants and
fusions:PLCG1mutants and
fusions:PLCG1mutants and
fusions:PLCG1bound to
FGF23:Klothowith enhanced
kinase activitywith enhanced
kinase activitywith enhanced
kinase activityenhanced kinase
activitydimers bound to
FGFsdimers bound to
FGFsdimers bound to
FGFsdimer:SPRED1/2
dimer(A:C):S112/S115
p-SPRY2(A:C):S112/S115
p-SPRY2SPRY2 has also been shown to be phosphorylated at multiple tyrosine residues in its C-terminal in response to FGF, but not EGF, stimulation. This phosphorylation, in particular at residue 227, is thought to augment the ability of SPRY2 to inhibit FGF signaling through the MAPK cascade, although the mechanism remains to be elucidated.
Somatic mutations in FGFR1 at P252 have also been identified in melanoma (P252S; Ruhe, 2007) and in lung cancer (P252T; Davies, 2005). Based on analogy to the FGFR1 P252R mutation that is found in Pfeiffer syndrome, these mutations are also predicted to increase the ligand-binding affinity of the receptor and to result in increased signaling, although this remains to be directly demonstrated for the S/T alleles (Ibrahimi, 2004a).
The FGFR1 K656E (TCGA, 2008) mutation is paralogous to activating mutations in FGFR3 kinase domain associated with the development of thanatophoric dysplasias (Tavormina, 1999; Bellus, 2000; Hart, 2000), and has itself been shown to activating when expressed in neural crest cells (Petiot, 2002).
The FGFR1 R576W (Rand, 2005) mutation increases the hydrophobicity of the receptor, and is postulated to enhance protein-protein interactions and thereby increase the likelihood of autophosphorylation of adjacent tyrosine residues, although this has not been explicitly demonstrated.
KAL1 consists of an N-terminal cysteine rich domain, a whey acidic protein-like (WAP) domain, four fibronectin III (FnIII) repeats and a C-terminal histidine rich region. The N-terminal cysteine rich region, the WAP domain and the first FnIII domain contribute to the interaction with the D2 and D3 Ig-like domains of FGFR1c. D1 and the acid box of the receptor inhibit the interaction with KAL1 in a manner analogous to the inhibition of FGF binding (Hu et al, 2009). Consistent with this, missense mutations in D1 and the acid box that affect the interaction with KAL1 have been identified in patients with Kallmann syndrome (Dode and Hardelin, 2009). Similarly, loss-of function mutations in the FnIII domain of KAL1 that disrupt the interaction with FGFR1c have also been characterized (Hu et al, 2009; Robertson et al, 2001; Gonzalez-Martinez et al 2004; Oliviera et al, 2001).
In the absence of serine phosphorylation, phosphorylation of Tyr55 and subsequent binding to E3 ubiquitin ligase, CBL, is enhanced. Serine phosphorylation of Sprouty2 appears to stabilise the protein by interfering with its potential phosphorylation of Tyr55 (Sprouty2 appears to be a poor substrate for c-Src kinase) in response to growth factor stimulation.
inhibitors of
overexpressed FGFR1inhibitors of FGFR1
fusion mutantsfusion mutant
dimersfusion mutant
dimersfusion mutant
dimersfusion mutant
dimersfusion mutant
dimersfusion mutant
dimersfusion mutant
dimersmutant
dimers:PIK3R1mutant
dimers:PIK3R1