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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FP-1039 is an FGFR1c:Fc fragment that acts as a broad FGF- ligand trap. Developed by FivePrime therapeutics (http://www.fiveprime.com/index.php?option=com_content&view=article&id=222&Itemid=153), FP-1039 is in Phase I clinical trials in solid malignancies and in Phase II trials in endometrial cancer patients carrying the FGFR2 S252W or P253R alleles.
FP-1039 is an FGFR1c:Fc fragment that acts as a broad FGF- ligand trap. Developed by FivePrime therapeutics (http://www.fiveprime.com/index.php?option=com_content&view=article&id=222&Itemid=153), FP-1039 is in Phase I clinical trials in solid malignancies and in Phase II trials in endometrial cancer patients carrying the FGFR2 S252W or P253R alleles.
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.
This represents WT FGFR2 of either the IIIb or IIIc isoform that is found overexpressed in some cancers. Sites of tyrosine phosphorylation are marked as unknown to circumvent the numbering differences between the isoform variants.
This represents FGFR2 S267C of either the IIIb or IIIC isoform; as such, the positions for tyrosine phosphorylation are marked as unknown to circumvent the difference in numbering between isoforms.
This represents FGFR2 W290C of either the IIIb or IIIC isoform; as such, the positions for tyrosine phosphorylation are marked as unknown to circumvent the difference in numbering between isoforms.
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.
In this reaction, FGF receptor 2c 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. Two isoforms of FGFR2c generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets.
In this reaction, FGF receptor 2b 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. Two isoforms of FGFR2b generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets.
The intrinsic protein tyrosine kinase activity of the activated FGFR2b receptor leads to multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Two isoforms of FGFR2b generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets. Based on sequence alignment, FGFR2 contains all 8 of the cytoplasmic tyrosine residues identified in FGFR1.
The intrinsic protein tyrosine kinase activity of the activated FGFR2c receptor leads to multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Two isoforms of FGFR2c generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in autophosphorylation, but differ in their abilities to interact with downstream targets. Based on sequence alignment, FGFR2 contains all 8 of the cytoplasmic tyrosine residues identified in FGFR1.
Point mutations in FGFR2 that are thought to promote ligand-independent dimerization in the context of autosomal bone development disorders have also been identified in endometrial, ovarian, gastric and lung cancer (Greenman, 2007; Dutt, 2008; Davies, 2005; Byron, 2008; Byron, 2010, Pollock, 2007). Although functional studies on these mutations in FGFR2 in cancer cell lines is limited - only the S267P mutation identified in gastric cancer has been demonstrated biochemically to undergo ligand-independent dimerization (Anderson, 1998) - characterization of paralogous mutations in FGFR3 as well as in other mutations that create unpaired cysteine residues in FGFR2 support the notion that these mutant receptors undergo aberrant intermolecular disulphide bond formation that results in constitutive activation (Galvin, 1996; Neilson and Friesel,1995; Robertson, 1998; d'Avis, 1998)
FGFR2 S267P undergoes ligand-independent dimerization, and appears unable to stably bind FGF2 ligand under the conditions examined (Anderson, 1998). FGFR2b S373C and Y376C are paralogous to the FGFR3 S371C and Y373C mutations that are seen in thanatophoric dysplasia I (Rousseau, 1996; Tavormina, 1995a) and which have been shown to undergo spontaneous dimerization in the absence of ligand (d'Avis, 1998; Adar, 2002). Moreover, other FGFR2 mutations that introduce unpaired cysteine residues have been shown to support formation of intermolecular disulphide bonds (Galvin, 1996; Neilson and Friesel, 1995), supporting the notion that the FGFR2b S373C and Y376C mutants may promote spontaneous receptor dimerization and activation.
Overexpressed FGFR2 in gastric and breast cancer cells has been shown to undergo ligand-independent dimerization (Takeda, 2007; Kunii, 2008; Moffa, 2004; Turner, 2010). Full-length FGFR2 is weakly transforming in NIH 3T3 cells, and is thought to possess a transformation-inhibiting domain in the C-terminus (Itoh, 1994). Interestingly, many cancers with amplifications of FGFR2 show preferrential expression of C-terminally truncated FGFR2 variants, designated C2 and C3, with 788 or 769 residues instead of the wild-type 822 (Hattori, 1990; Itoh, 1994; Ueda, 1999). These variants, which lack a number of carboxy-terminal tyrosine residues, show increased transforming potency compared to the full-length receptor (Cha, 2008; Cha, 2009), and have been shown to be constitutively active and to dimerize spontaneously (Takeda, 2007).
Amplification of full length FGFR2 is only weakly transforming in NIH 3T3 cells, reflecting the presence of a putative transformation-inhibitory region in the c-terminus of the protein (Itoh, 1994, Cha, 2009). C-terminally truncated variants of FGFR2 that are preferrentially expressed in cancer show more potent transformation potential (Cha, 2008; Cha, 2009). These variants lack a number of carboxy-terminal tyrosine residues, including Y770 and Y773. Loss of Y770 contributes to transformation by enhancing FRS2 binding to the C-terminally truncated variant. This suggests that in the context of the full-length protein the presence of Y770 restricts access of FRS2 to the receptor. Loss or mutation of Y773 impairs internalization and degradation of the receptor and promotes sustained signaling (Cha, 2009). Gastric cancer cell lines with FGFR2 amplifications appear to undergo ligand-independent signaling and are sensitive to inhibition with ATP-competitive inhibitors (Takeda, 2007).
FGFR2 amplifications identified in 4% of triple negative breast cancers have also been shown to be constitutively active and to have elevated levels of phosphorylated FRS2 in the absence of ligand. Consistent with this, shRNA knockdown or chemical inhibition restricts proliferation and induces apoptosis in these cells (Kunii, 2008; Turner, 2010)
Amplified FGFR2 has been shown to be a potential target for a number of ATP-competitive inhibitors, some of which are currently in clinical trials for therapeutic use (Takeda, 2007; Turner, 2010; http://clinicaltrials.gov).
Mutations in the highly conserved Pro-Ser dipeptide repeat of FGFR2 have been identified both in Apert syndrome and in endometrial and ovarian cancers (Wilkie, 1995; Dutt, 2008; Pollock, 2007; Byron, 2010). Missense S252W or P253R mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). In the context of endometrial cancer, these mutations are mutually exclusive with KRAS mutations, but are associated at high frequency with PTEN mutations (Byron, 2008). The S252W and P253R mutations allow the receptor to bind to an expanded range of ligands, such that the mesenchymal splice form (FGFR2c) is anomalously activated by the mesenchymal ligands FGF7 and FGF10, establishing an autocrine signaling loop. These mutations also increase the binding affinity for the receptor's normal epithelial ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).
Apert sydrome is the most severe of the craniosynostosis syndromes and results almost entirely from two missense mutations in the conserved Ser252 and Pro253 residues in the IgII-IgIII linker of FGFR2 (Wilkie, 1995). These mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). More recently, the same mutations arising somatically have been identified in endometrial and ovarian cancer (Dutt, 2008; Byron, 2008; Pollock, 2007).
The IgII and IgIII domains and the intervening linker of the FGF receptor constitute a binding site for FGFs (Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999). The epithelial isoform FGFR2b binds only to mesenchymally expressed ligands including FGF7 and FGF10 and does not respond to epithelial ligands FGF2, 4, 6, 8 and 9 (Ornitz, 1996). Introduction of the P252W and P252R mutations into FGFR2b allows the aberrant binding and activation by the epithelially expressed ligands FGF 2, 6 and 9, establishing an autocrine signaling loop in epithelial cells. These mutations also increase the binding affinity for the receptor's normal mesenchymal ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).
Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998). Due to the highly conserved nature of these residues across all four FGF receptors, it is generally believed that these germline mutations in FGFR2 are also activating, though this remains to be demonstrated experimentally.
As further support of this notion, activating point mutations in the kinase domain of FGFR2 have also been identified in endometrial, uterine and cervical cancers (Pollock, 2007; Dutt, 2008), and in some cases have been shown to have enhanced kinase activity and to support anchorage-independent growth in NIH 3T3 cells (Dutt, 2008). Knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival (Dutt, 2008; Byron, 2008). Kinase-domain mutants show elevated levels of activity relative to the wild-type even in the absence of receptor phosphorylation, and although their kinase activity is further enhanced upon trans-autophosphorylation, the extent of this is less than that seen in the wild-type, suggesting that the mutant alleles are capable of of supporting ligand-independent activation (Chen, 2007)
After aberrantly dimerizing in response to mesenchymally expressed ligands, FGFR2c S252W and P253R mutants are assumed to undergo transautophosphorylation analagous to the wild-type receptor, although this has not been explicitly demonstrated. Knock-down or chemical inhibition of other FGFR2-activating mutations identified in endometrial cancer cells has been shown to cause cell death (Byron, 2008).
After aberrantly dimerizing in response to epithelially expressed ligands, FGFR2b S252W and P253R mutants are assumed to undergo transautophosphorylation analagous to both the wild-type receptor, although this has not been explicitly demonstrated. Transformation of NIH 3T3 cells with the FGFR2b S252W mutant confers anchorage independent growth and results in increased phosphorylation of FRS2 in a manner that depends on a functional kinase domain (Dutt, 2008). Knock-down or chemical inhibition of other FGFR2-activating mutations identified in endometrial cancer cells has been shown to cause cell death (Byron, 2008).
Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations identified in FGFR2 in craniosynostosis disorders are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998).
Characterization of FGFR2 proteins containing somatic mutations at these residues support the notion that they have elevated levels of kinase activity. FRS2 is constitutively phosphorylated in the FGFR2 N549K kinase mutant identified in endometrial tumors and knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival. FGFR2 knockdown also results in a significant decrease in the levels of phosphorylated Erk1/2 (Dutt, 2008; Byron, 2008; Pollock, 2007). Crystal structures of FGFR2 kinase mutants N549H and K650N show that the mutations disengage an 'auto-inhibitory brake' on the kinase domain of the receptor. Biochemically, the FGFR2 N549K and K660E mutants show elevated kinase activity relative to the unphosphorylated wild-type protein and have increased activity towards peptide substrates; this activity is stimulated upon receptor phosphorylation, but to a lesser extent than seen with the wild-type receptor (Chen, 2007).
Treatment of FGFR2-amplified gastric and breast cancer cell lines with the antibody GP369 inhibits FGFR2 phosphorylation and downstream signaling and suppresses cell proliferation. Treatment of mice with GP369 inhibits the growth of human cancer xenografts carrying activating FGFR2 mutations. The GP369-binding epitope is contained in the ligand-binding region of the receptor, suggesting that the antibody works by disrupting the ligand-dependent activation of amplified FGFR2 (Bai, 2010).
FP-1039 is a soluble fusion protein consisting of the extracellular region of FGFR1c bound to the Fc region of human IgG1. It is capable of binding to a wide range of FGF ligands and thereby prevents activation of multiple FGF receptors. FP-1039 is in Phase I clinical trials in solid malignancies and in Phase II trials for patients with endometrial cancers harbouring the activating mutations S252W and P253R (reviewed in Wesche, 2011).
FGFR2 is inhibited by a range of in vitro tyrosine kinase inhibitors, including PD170734 and SU5402 (reviewed in Greulich and Pollock, 2010; Wesche, 2011). In addition, there are a number of FGFR2 inhibitors currently in clinical trials that for treatment of solid malignancies (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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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).
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.
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 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.
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.
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.
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.
Fibroblast growth factor binding proteins (FGFBPs) are extracellular proteins that bind to FGFs and extract them from the extracellular matrix, thereby increasing their mitogenic potential (Wu et al, 1991; Tassi et al, 2001; Beer et al, 2005; reviewed in Abuharbeid et al, 2005). FGFBP1 has been shown to bind to FGF1, 2, 7, 10 and 22 by co-immunoprecipitation and/or competition assay (Tassi et al, 2001; Beer et al, 2005). Furthermore, it has been shown that stimulation of FGF7 along with FGFBP1 enhances the proliferation of FGFR2b-expressing cells (Beer et al, 2005). FGFBP expression is upregulated in some cancers and contributes to tumor growth and angiogenesis (reviewed in Abuharbeid et al, 2005).
Repression of FGFR2 exon IIIb splicing in mesenchymal cells depends on intronic splicing silencer (ISS) sequences upstream of exon IIIb as well as an exonic splicing element (ESE) within exon IIIb. These elements are bound by PTB1 and hnRNPA1, respectively, as part of a larger splicing complex, promoting the formation and expression of mature FGFR2c mRNA in mesenchymal cells (Carstens et al, 2000; Gil et al, 1991; Del Gatto et al, 1997; Del Gatto et al, 1999). For more detailed information on splicing and pre-mRNA maturation, please see the mRNA splicing pathway.
Expression of FGFR2 IIIb splice variant is characteristic of epithelial cells. A number of cis-acting elements have been identified in the FGFR2 pre-mRNA that are required for correct expression of the IIIb isoform and repression of the mesenchymal IIIc form (Muh et al, 2002; Hovhannisyan and Carstens, 2005; Hovhannisyan et al, 2006). These include the ISAR and ISE/ISS elements 1-3 in the region between exon 8 and exon 9 of the pre-mRNA. ESRP1 and ESRP2 are RNA-binding mRNA splicing factors that promote epithelial-specific IIIb splicing by binding to the ISE/ISS-3 sequence (Warzecha et al, 2009). A complex of RBFOX2, hnRNPH1 and hnRNPF may cooperate with the ESRP proteins to stimulate IIIb-specific splicing by binding to adjacent exonic GGG motifs (Baraniak et al, 2006; Mauger et al, 2008). This RBFOX2-hnRNP complex appears to compete with the IIIc-promoting trans-acting factor ASF/SF2 for binding to these exonic sites (Mauger et al, 2008). Other factors that appear to contribute to IIIb-specific splicing include hnRNPM, TIA1 and TIAL1, although their precise roles remain to be elucidated (Hovhannisyan and Carstens, 2007; Del Gatto-Konczak et al, 2000; Newman et al, 2006).
In epithelial cells, FGFR2 IIIb-specific alternative splicing is favoured by the binding of ESRP1 and 2, RBFOX2, TIA1 and TIAL1 to the nascent transcript. These proteins, in conjunction with other splicing factors, activate exon IIIb-specific splicing and repress exon IIIc-specific splicing (Warzecha et al, 2009; Baraniak et al, 2006; Mauger et al, 2008; Hovhannisyan and Carstens, 2007; Del Gatto et al, 2000).
In mesenchymal cells, FGFR2 IIIc exon splicing is favoured by the binding of PTB1 to intronic splice silencer (ISS) sequences 1 and 2 that flank the IIIb specific exon, and by the binding of hnRNPA1 to an exonic splicing silencer (ESS) within the IIIb specific exon (Del Gatto-Konczak et al, 1999; Carstens et al, 2000). Binding of these proteins to the nascent mRNA , which occurs in the context of a larger splicing complex, represses IIIb-specific alternative splicing and favours the formation of FGFR2 IIIc-specific mRNA.
A secreted truncated form of FGFR2 known as IIIa TM is produced and stable in a mouse model of Apert Syndrome. FGFR2 IIIa TM is formed from aberrant splicing of FGFR2 exon 7 (IIIa) into exon 10 (containing the transmembrane domain). In WT cells, this transcript is degraded by nonsense-mediated decay, but persists in the disease model by an unknown mechanism. FGFR IIIa TM modulates the binding of FGF1 to FGFR2 in vitro and negatively regulates FGFR2 signaling in vitro and in vivo (Wheldon et al, 2011).
FGFR2 fusions in cholangiocarcinoma and cancers of the breast, lung and thyroid have been shown to promote anchorage independent growth, cellular proliferation and tumorigenesis. In some cases, such as for FGFR2-AHCYL1 and FGFR2-BICC1 fusions in cholangiocarcinoma, these activities have been shown to depend on the FGFR2 kinase domain, suggesting that the fusions undergo autophosphorylation after oligomerization, as is the case for WT FGFR2. FGFR2 fusions, where tested, also show sensitivity to kinase inhibitors such as PD173074 and pazopanib (Arai et al, 2013; Wu et al, 2013; Seo et al, 2012; reviewed in Parker et al, 2014).
FGFR2 fusions have been identified in a number of cancers, including breast, thyroid, lung and cholangiocarcinoma (Wu et al, 2013; Seo et al, 2012; Arai et al, 2013; reviewed in Parker et al, 2014). Many of the 3' fusion partners contain dimerization domains, suggesting the fusion proteins may dimerize contstitutively independent of ligand binding, although this has not been explicitly demonstrated in all cases (Wu et al, 2013; reviewed in Parker et al, 2014).
By BIAcore assay, FGFR2 IIIa TM has been shown to bind FGF1, and in the presence of chip-bound FGFR2b or 2c, to form an FGF1-dependent heterodimer. In COS cells stimulated with FGF2, expression of FGFR IIIa TM abrogates FGF signaling and stabilizes the full length receptors at the cell surface. Consistent with this, in vivo expression of FGFR2 IIIa TM abrogates expression of the FGFR target gene MKP3. These data support the idea that FGFR2 IIIa TM inhibits FGFR signaling by binding and sequestering ligand and/or forming non-functional heterodimers with full-length receptors (Wheldon et al, 2011).
RAS nucleotide is stimulated downstream of activated FGFR2 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 FGFR2
dimersligand-independent
mutantsmutants with enhanced kinase
activityhomodimer bound to
FGFmutants with enhanced ligand
bindinghomodimer bound to
FGFmutants with enhanced
ligand-bindingligand-independent
mutant dimersligand-independent
mutantswith enhanced
kinase activityenhanced kinase
activityTM:FGF1,2:FGFR2b,
FGFR2cmutant-binding
FGFs:FP-1039with enhanced ligand-binding
bound to FGFsenhanced ligand
bindingwith enhanced ligand-binding
bound to FGFsenhanced ligand
binding(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 FGFR2inhibitors of FGFR2
mutantspre-FGFR2 mRNA:CBC
complexAnnotated Interactions
overexpressed FGFR2
dimersligand-independent
mutantsmutants with enhanced kinase
activityhomodimer bound to
FGFmutants with enhanced ligand
bindinghomodimer bound to
FGFmutants with enhanced
ligand-bindingligand-independent
mutant dimersligand-independent
mutant dimersligand-independent
mutant dimersligand-independent
mutantswith enhanced
kinase activitywith enhanced
kinase activitywith enhanced
kinase activityenhanced kinase
activityTM:FGF1,2:FGFR2b,
FGFR2cmutant-binding
FGFs:FP-1039with enhanced ligand-binding
bound to FGFswith enhanced ligand-binding
bound to FGFswith enhanced ligand-binding
bound to FGFsenhanced ligand
bindingwith enhanced ligand-binding
bound to FGFswith enhanced ligand-binding
bound to FGFswith enhanced ligand-binding
bound to FGFsenhanced ligand
binding(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.
FGFR2 amplifications identified in 4% of triple negative breast cancers have also been shown to be constitutively active and to have elevated levels of phosphorylated FRS2 in the absence of ligand. Consistent with this, shRNA knockdown or chemical inhibition restricts proliferation and induces apoptosis in these cells (Kunii, 2008; Turner, 2010)
The IgII and IgIII domains and the intervening linker of the FGF receptor constitute a binding site for FGFs (Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999). The epithelial isoform FGFR2b binds only to mesenchymally expressed ligands including FGF7 and FGF10 and does not respond to epithelial ligands FGF2, 4, 6, 8 and 9 (Ornitz, 1996). Introduction of the P252W and P252R mutations into FGFR2b allows the aberrant binding and activation by the epithelially expressed ligands FGF 2, 6 and 9, establishing an autocrine signaling loop in epithelial cells. These mutations also increase the binding affinity for the receptor's normal mesenchymal ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).
As further support of this notion, activating point mutations in the kinase domain of FGFR2 have also been identified in endometrial, uterine and cervical cancers (Pollock, 2007; Dutt, 2008), and in some cases have been shown to have enhanced kinase activity and to support anchorage-independent growth in NIH 3T3 cells (Dutt, 2008). Knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival (Dutt, 2008; Byron, 2008). Kinase-domain mutants show elevated levels of activity relative to the wild-type even in the absence of receptor phosphorylation, and although their kinase activity is further enhanced upon trans-autophosphorylation, the extent of this is less than that seen in the wild-type, suggesting that the mutant alleles are capable of of supporting ligand-independent activation (Chen, 2007)
Characterization of FGFR2 proteins containing somatic mutations at these residues support the notion that they have elevated levels of kinase activity. FRS2 is constitutively phosphorylated in the FGFR2 N549K kinase mutant identified in endometrial tumors and knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival. FGFR2 knockdown also results in a significant decrease in the levels of phosphorylated Erk1/2 (Dutt, 2008; Byron, 2008; Pollock, 2007). Crystal structures of FGFR2 kinase mutants N549H and K650N show that the mutations disengage an 'auto-inhibitory brake' on the kinase domain of the receptor. Biochemically, the FGFR2 N549K and K660E mutants show elevated kinase activity relative to the unphosphorylated wild-type protein and have increased activity towards peptide substrates; this activity is stimulated upon receptor phosphorylation, but to a lesser extent than seen with the wild-type receptor (Chen, 2007).
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 FGFR2inhibitors of FGFR2
mutantspre-FGFR2 mRNA:CBC
complexpre-FGFR2 mRNA:CBC
complexpre-FGFR2 mRNA:CBC
complexpre-FGFR2 mRNA:CBC
complexpre-FGFR2 mRNA:CBC
complex