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Originally published In Press as doi:10.1074/jbc.C700130200 on August 21, 2007

J. Biol. Chem., Vol. 282, Issue 40, 29069-29072, October 5, 2007
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Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling*

Xinle Wu{ddagger}, Hongfei Ge{ddagger}, Jamila Gupte{ddagger}, Jennifer Weiszmann{ddagger}, Grant Shimamoto§, Jennitte Stevens§, Nessa Hawkins§, Bryan Lemon{ddagger}, Wenyan Shen{ddagger}, Jing Xu§, Murielle M. Veniant2, Yue-Sheng Li§, Richard Lindberg§, Jin-Long Chen{ddagger}, Hui Tian{ddagger}, and Yang Li{ddagger}1

From the {ddagger}Amgen Inc., South San Francisco, California 94080 and §Amgen Inc., Thousand Oaks, California 91320

Received for publication, July 2, 2007 , and in revised form, August 14, 2007.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSIONS
 REFERENCES
 
FGF19 is a unique member of the fibroblast growth factor (FGF) family of secreted proteins that regulates bile acid homeostasis and metabolic state in an endocrine fashion. Here we investigate the cell surface receptors required for signaling by FGF19. We show that betaKlotho, a single-pass transmembrane protein highly expressed in liver and fat, induced ERK1/2 phosphorylation in response to FGF19 treatment and significantly increased the interactions between FGF19 and FGFR4. Interestingly, our results show that {alpha}Klotho, another Klotho family protein related to betaKlotho, also induced ERK1/2 phosphorylation in response to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of betaKlotho. In addition, heparin further enhanced the effects of both {alpha}Klotho and betaKlotho in FGF19 signaling and interaction experiments. These results suggest that a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either {alpha}Klotho or betaKlotho.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSIONS
 REFERENCES
 
The fibroblast growth factors (FGFs)2 constitute a structurally related family of 22 proteins (1). This family of secreted proteins has been implicated in a variety of functions including angiogenesis, mitogenesis, vertebrate and invertebrate development, cellular differentiation, wound healing/repair, and metabolic regulations (2, 3). FGFs can be grouped into seven subfamilies based on their sequence similarities and functional properties (4). Four tyrosine kinase receptors have been identified for FGFs (FGFR1–4), each containing an extracellular ligand binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain (5). Alternative RNA splicing of one of two unique exons in FGFR1–3 results in the two different, b and c, receptor isoforms (2). Because most FGFs only function in an autocrine or paracrine fashion, the tissue distribution of these FGFs determines the tissue specific functions for most of the FGF family members (2, 4).

The FGF19 subfamily contains three members, FGF19, FGF21, and FGF23. In contrast to other FGFs, which require heparin or heparan sulfate for high affinity receptor binding and activation, FGF19 subfamily members do not bind heparin with high affinity (6). In addition, FGF19 subfamily members contain intramolecular disulfide bonds, which may function to increase their stability in plasma and allow them to function as hormones (7). Indeed, although FGF19 is not expressed in liver or gallbladder, it can regulate hepatic bile acid metabolism and control gallbladder filling (8–11). Furthermore, transgenic animals overexpressing FGF19 from skeletal muscle and animals injected with recombinant protein display improved insulin sensitivity, reduced adiposity, and increased metabolic rate (12, 13). In addition, FGF21 has been shown to regulate glucose and lipid metabolism in an endocrine fashion (14), and FGF23 may function as a phosphaturic hormone (15). These unique features of the FGF19 subfamily suggest that they may interact with their receptors differently from the canonical FGFs and may require different receptor complexes to function.

The unique receptor requirements were first noted from studies with FGF23 (16, 17). The {alpha}Klotho gene encodes a 130-kDa single-pass transmembrane protein with a short cytoplasmic domain. Since FGF23-deficient mice (Fgf23–/– mice) and {alpha}Klotho-deficient mice ({alpha}Kloth–/– mice) share remarkable similarity in phenotypes, including shortened life span, growth retardation, infertility, muscle atrophy, hypoglycemia, and vascular calcification in the kidneys (18, 19), it was hypothesized that FGF23 and {alpha}Klotho function through a common signal transduction pathway. Direct evidence for {alpha}Klotho as a co-receptor for FGF23 came from recent biochemical and cellular studies (16, 17). It was shown that although FGF23 alone has poor affinity for FGFRs and did not promote efficient activation of FGFRs in cells, {alpha}Klotho was able to function as an essential cofactor for the activation of FGFR signaling by FGF23. This suggests that FGF23 binds an {alpha}Klotho-FGFR complex with higher affinity than to either receptor alone. Coexpression of {alpha}Klotho in HEK293 and Chinese hamster ovary cells significantly enhanced the ability of FGF23 to induce phosphorylation of FGF receptor substrate and ERK1/2 in these cells (16, 17). Similar observations have recently been reported for FGF21. Instead of requiring {alpha}Klotho as a cofactor, FGF21 utilizes another Klotho family protein, betaKlotho, as a coreceptor for signaling (20). Therefore, the presence of betaKlotho confers high affinity binding of FGF21 to FGFRs and allows cells coexpressing betaKlotho and FGFRs to respond to FGF21 and activate signal transduction pathways.

Although earlier observations suggest that heparin has low affinity interaction with FGF19 and may act as a weak cofactor for FGF19 (21), whether additional factors were required or could modulate FGF19-FGFR interactions and the effect of heparin on receptor complex formation have not been defined. Here, we show that both {alpha}Klotho and betaKlotho may function as coreceptors for FGF19. The presence of {alpha}Klotho or betaKlotho together with relatively high concentrations of heparin confers the strongest binding of FGF19 to FGFR and results in the highest level of ERK1/2 phosphorylation following receptor activation.


   EXPERIMENTAL PROCEDURES
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSIONS
 REFERENCES
 
Plasmids and Proteins—Full-length human betaKlotho, {alpha}Klotho, and extracellular domains of human betaKlotho and {alpha}Klotho were cloned into the pTT14 expression vector. pFA2-Elk1 and pFR-Luc plasmids used in the ERK luciferase reporter assay were from Stratagene. Renilla luciferase, pRL-TK (Promega), was used as an internal control reporter. Recombinant FGF19 and FGFR-Fc fusion proteins were purchased from R&D.

Cell Culture and Transfections—HEK293 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and penicillin/streptomycin. Cells were transfected with the expression vector plasmids using the Lipofectamine 2000 transfection reagent (Invitrogen) according to the manufacturer's protocol.

Conditioned Medium Preparation—HEK293 cells were transfected with expression vectors encoding the extracellular domains of betaKlotho and {alpha}Klotho, and the medium was collected 3 days after transfection. Expression of soluble betaKlotho and {alpha}Klotho was confirmed by Western blot using anti-betaKlotho and anti-{alpha}Klotho antibodies (R&D). Medium from cells transfected with vector encoding green florescent protein (GFP) was also collected as a negative control.

Pull-down Assay—To analyze the interaction between FGF19 and FGF receptors, recombinant FGF19 (0.5 µg) was mixed with FGFR1c-Fc, FGFR2c-Fc, FGFR3c-Fc, or FGFR4-Fc fusion proteins (0.5 µg) in conditioned medium and applied to 50 µl of protein G-Sepharose at 4 °C for 2 h. The beads were washed three times with phosphate-buffered saline and then suspended in SDS sample buffer and subjected to Western blot analysis with anti-FGF19 antibody (R&D).

ERK Activation Reporter Assay—HEK293 cells were seeded in 96-well plates (105 cells/well). For each well, the transfection was done by mixing 10 ng of pFA2-Elk1, 150 ng of pFR-Luc, and 10 ng of pRL-TK reporter plasmids and 150 ng of betaKlotho expression vector in 25 µl of OptiMEM (Invitrogen) with 0.5 µl of Lipofectamine 2000 in 25 µl of OptiMEM. On the following day, the cells were cultured in Dulbecco's modified Eagle's medium without serum but with 0.2% bovine serum albumin overnight. The cells were incubated with various concentrations of FGF19 for 5 h, and the luciferase activity was measured using DualGlo (Promega), according to the manufacturer's instructions.

Western Blot Analysis of the FGF Signaling Pathway—HEK293 cells were transfected in 6-well plates and starved in serum-free medium overnight the day after transfection. For heparitinase treatment, 0.2 units/ml heparitinase (Sigma) was incubated with the cells for 3 h before FGF19 was added. After treatment with various concentrations of recombinant human FGF19 for 15 min, cells were snap-frozen in liquid nitrogen, and cell lysates were prepared in SDS sample buffer and subjected to Western blot analysis using anti-phospho-p44/42 mitogen-activated protein (MAP) kinase (anti-phospho-ERK1/2) antibody (Cell Signaling) and anti-ERK antibody (Cell Signaling).


Figure 1
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  		FIGURE 1.
FGF19 activates HEK293 cells transfected with betaKlotho in ERK1/2 luciferase reporter assay. HEK293 cells were transfected with pFA2-Elk1, pFR-Luc, and pRL-TK luciferase reporter plasmids and betaKlotho expression vector or GFP control. After starving the cells overnight in Dulbecco's modified Eagle's medium plus 0.2% bovine serum albumin, various concentrations of FGF19 were added, and the luciferase activity was measured after 5 h. Heparin was added just before FGF19 treatment. Maximal heparin response was obtained at 20 µg/ml, and further increasing heparin concentrations up to 200 µg/ml had no additional effects.

 

   RESULTS AND DISCUSSIONS
TOP
 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSIONS
REFERENCES
 
betaKlotho and Heparin Enhance FGF19 Activation of FGFR Signaling—Since betaKlotho is highly expressed in the liver and mice deficient in betaKlotho exhibit a dramatic elevation of bile acid synthesis, we tested the possibility that betaKlotho might function as a co-receptor for FGF19. We used a luciferase reporter assay system based on ERK1/2 phosphorylation (22) to test the activation of the FGF signaling pathway by FGF19 in HEK293 cells, which normally do not respond to FGF19 treatment. In HEK293 cells transfected with only control GFP vector, FGF19 did not activate any luciferase reporter expression (Fig. 1). To test whether betaKlotho is required for FGF19 activation of FGF signaling, we transfected HEK293 cells with full-length human betaKlotho and stimulated the cells with various concentrations of FGF19. As shown in Fig. 1, betaKlotho-expressing cells responded to FGF19 in a dose-dependent manner with an EC50 value of 54 nM. Although FGF19 has been reported to have significantly lower heparin binding affinity (6), adding heparin at a relatively high concentration of 20 µg/ml to the cells further enhanced the FGF19 response (Fig. 1). Heparin alone at this concentration had no effect on the reporter expression (Fig. 1). These results suggest that FGF19 may signal through the complex formed by betaKlotho, heparin, and FGF receptors.

betaKlotho and Heparin Enhance the Binding of FGF19 to FGFR4—The mammalian FGFRs are encoded by four distinct genes (FGFR1 through FGFR4). A major alternative mRNA splicing event within one of the three immunoglobulin-like extracellular domains of FGFR1–3 generates the b and c isoforms. It has been shown that both betaKlotho and {alpha}Klotho preferentially bind to the c isoforms of FGFR1–3 and FGFR4 (17, 20). FGF21 interacted with FGFR1c, FGFR2c, and FGFR4 complexed with betaKlotho (20), and FGF23 interacted with FGFR1c, FGFR3c, and FGFR4 complexed with {alpha}Klotho (17). To investigate the effects of betaKlotho and heparin on the binding of FGF19 to the various FGFRs, we used pull-down experiments to test whether FGF19 can be co-precipitated by Fc-FGFR fusion proteins complexed to protein G beads. In the presence of 20 µg/ml heparin, we demonstrated the binding of FGF19 to FGFR4 but did not detect significant binding to FGFR1c, FGFR2c, and FGFR3c (Fig. 2A, left panel). When conditioned medium containing the extracellular domain of betaKlotho was added to the immunoprecipitation reaction, the FGF19-FGFR4 interaction was increased, but still no significant interactions could be observed between FGF19 and the other FGFRs (Fig. 2A, right panel). These results are consistent with the previous findings that FGF19 specifically interacts with FGFR4 (21); however, they do not necessarily rule out interactions between FGF19 and other receptors under different conditions. To further dissect the individual roles played by betaKlotho and heparin on the interactions between FGF19 and FGFR4, we tested the additional combination of heparin and betaKlotho. In the absence of betaKlotho and heparin, no significant interactions were observed between FGF19 and FGFR4 (Fig. 2B, left panel). The addition of either soluble betaKlotho conditioned media or heparin alone increased the interaction between FGF19 and FGFR4 (Fig. 2B, middle two panels). The strongest signal was detected when both betaKlotho and heparin were present in the immunoprecipitation solution (Fig. 2B, right panel). These results suggest that although either betaKlotho or heparin alone could potentiate interactions between FGF19 and FGFR4, together they show an even greater effect and perhaps may work synergistically with FGFR4 to provide the high affinity receptor complex for FGF19.


Figure 2
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  		FIGURE 2.
FGF19 interaction with FGFRs requires both betaKlotho and heparin. A, FGF19 binds to FGFR4. Interactions between FGF19 and Fc-FGF fusion receptors were analyzed by a pull-down assay. In the presence of 20 µg/ml heparin and soluble betaKlotho, FGF19 binds to FGFR4. The left panel and the right panel are on the same gel with the same exposure. 1c, FGFR1c; 2c, FGFR2c; 3c, FGFR3c; 4, FGFR4. B, FGF19 requires either heparin or betaKlotho to bind to FGFR4. betaKlotho is needed for the binding between FGF19 and FGFR4 in the absence of heparin. Heparin alone can also enhance the interaction between FGF19 and FGFR4.

 
{alpha}Klotho May Also Potentiate FGF19 Signaling—The Klotho component requirements for FGF21 and FGF23 co-receptor complexes appear very specific; FGF21 only works through betaKlotho, and FGF23 only works through {alpha}Klotho (16, 17, 20). We wanted to test the specificity of FGF19 toward the Klotho proteins. An experiment similar to that performed for betaKlotho (Fig. 2B) was also established for {alpha}Klotho. In the absence of {alpha}Klotho and heparin, similar to the results seen in Fig. 2B, no significant interaction was observed between FGF19 and FGFR4 (Fig. 3, left panel). The addition of either soluble {alpha}Klotho conditioned medium or heparin alone increased the interactions between FGF19 and FGFR4 (Fig. 3, middle two panels). Again, similar to what was observed for betaKlotho, the strongest signal was detected when both {alpha}Klotho and heparin were present in the immunoprecipitation solution (Fig. 3, right panel). These results suggest that, in contrast to FGF21 and FGF23, which are specific for one form of Klotho protein, FGF19 is able to interact with FGFR complexes that are formed with either {alpha}Klotho or betaKlotho.


Figure 3
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  		FIGURE 3.
{alpha}Klotho enhances the binding of FGF19 to FGFR4. FGFR4 can interact with FGF19 in the pull-down assay in the presence of either {alpha}Klotho or heparin.

 


Figure 4
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  		FIGURE 4.
FGF19 actives ERK1/2 phosphorylation in HEK293 cells transfected with{alpha}Klotho orbetaKlotho. HEK293 cells were transfected with expression vectors for {alpha}Klotho or betaKlotho. After being starved with serum-free medium overnight, the cells were stimulated with vehicle or 50 nM recombinant FGF19 for 15 min and snap-frozen in liquid nitrogen. Heparin (20 µg/ml) was added just before the FGF19 treatment. Cell lysates were processed for Western blot with antibodies against phosphorylated ERK1/2 (pERK1/2) or total ERK1/2 (ERK1/2).

 
To further investigate the role {alpha}Klotho plays in FGF19 signaling, we used Western blotting to measure ERK1/2 phosphorylation in HEK293 cells transfected with {alpha}Klotho or betaKlotho treated with recombinant FGF19. As shown in Fig. 4, unlike FGF21 and FGF23, which only respond to one of the Klotho proteins (16, 17, 20), FGF19 is able to activate ERK1/2 phosphorylation in cells transfected with either betaKlotho or {alpha}Klotho (Fig. 4). Heparin also seemed to stimulate ERK1/2 phosphorylation in the presence of {alpha}Klotho as it did in the presence of betaKlotho (Figs. 2B and 4). FGF19 was not able to activate ERK1/2 phosphorylation in HEK293 cells without Klotho proteins (Fig. 1 and data not shown). Therefore, it appears that at least in vitro, FGFRs/heparin complexed with either betaKlotho or {alpha}Klotho may serve as receptor complexes for FGF19.

Both heparin and heparan sulfate are known to stimulate FGF signal transduction by increasing the affinity between the FGFs and FGFRs (23); however, only heparan sulfate is present on cell surfaces. In our pull-down assay, we also found that heparin enhanced the binding of FGF19 and FGFR4 independent of {alpha}Klotho or betaKlotho. However, in the ERK1/2 phosphorylation assay using HEK293 cells, FGF19 could not activate FGF signaling with heparin alone (Fig. 1). One potential explanation is that although either Klotho or heparin can stabilize the FGF19-FGFR complex, Klotho is fundamentally required for the activation of FGFR by FGF19, perhaps by inducing a specific conformation change in the receptor, which activates downstream signaling pathways. The other possibility is that the presence of endogenous heparan sulfate on the cell surface masked the effects of exogenously added heparin at the concentrations tested in the absence of Klotho proteins. To assess the possible contribution of endogenous heparan sulfate to the FGF19 signaling and provide evidence that the observed effects of heparin are physiologically relevant, we tested the effects of heparitinase treatment on FGF19-induced ERK1/2 phosphorylation in betaKlotho-transfected HEK293 cells. As shown in Fig. 5, heparitinase treatment significantly suppressed the FGF19 signaling in the absence of added heparin as observed by the reduced ERK1/2 phosphorylation levels. This result suggests that endogenous heparan sulfate could contribute to FGF19 signaling and that FGFRs/heparan sulfate complexed with Klotho may serve as receptor complexes for FGF19.


Figure 5
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  		FIGURE 5.
Effects of heparitinase treatment on FGF19 activation in HEK293 cells. HEK293 cells were transfected with expression vectors for betaKlotho. After being serum-starved overnight, cells were treated with 0.2 units/ml heparitinase for 3 h before being stimulated with 100 nM recombinant FGF19 for 15 min and snap-frozen in liquid nitrogen. Cell lysates were processed for Western blot with antibodies against phosphorylated ERK1/2 (pERK1/2) or total ERK1/2 (ERK1/2).

 
Mice deficient in betaKlotho share similar phenotypes with mice lacking either FGF15 (murine ortholog of human FGF19) or FGFR4 (9, 24). In the present study, we show that betaKlotho enables FGF19 to bind to FGFR4 and activate ERK phosphorylation. Our results strongly suggest that betaKlotho acts as a cofactor that converts a canonical FGFR into a specific receptor for FGF19. The expression pattern of betaKlotho may therefore restrict the action of FGF19 and thus confer the tissue-specific bioactivity on FGF19. This would be consistent with studies on the other two family members, FGF21 and FGF23 (16, 17, 20). We also discovered that under our in vitro assay conditions, FGF19 has specificity toward {alpha}Klotho as well as betaKlotho, although no apparent phenotypic overlapping between FGF19 and {alpha}Klotho has been reported. Such dual specificity was not found for FGF21 and FGF23 (16, 17, 20). The physiological relevance of FGF19 and {alpha}Klotho interactions will be a subject for future studies.


   FOOTNOTES
 
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Back

2 The abbreviations used are: FGF, fibroblast growth factors; FGFR, FGF receptor; ERK, extracellular signal-regulated kinase; GFP, green fluorescent protein. Back

1 To whom correspondence should be addressed: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080. Tel.: 650-244-2524; Fax: 650-837-9423; E-mail: yangl{at}amgen.com.


   ACKNOWLEDGMENTS
 
We thank Peter Coward, John Lamerdin, Margret Karow, Randy Hecht, Helen Kim, Fei Xiong, Jackie Sheng, and Tom Boone for helpful discussions and critical reading of the manuscript.



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 ABSTRACT
 INTRODUCTION
 EXPERIMENTAL PROCEDURES
 RESULTS AND DISCUSSIONS
 REFERENCES
 

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S. Siffroi-Fernandez, M.-P. Felder-Schmittbuhl, H. Khanna, A. Swaroop, and D. Hicks
FGF19 Exhibits Neuroprotective Effects on Adult Mammalian Photoreceptors In Vitro
Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1696 - 1704.
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