Co-receptor Requirements for Fibroblast Growth Factor-19 Signaling
Open accessAbstract
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 alphaKlotho, 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 alphaKlotho 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 alphaKlotho or betaKlotho.
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Loss of KLB abolishes all effects of FGF21 in vitro and in vivo.
“loss of KLB abolishes all effects of FGF21 in vitro and in vivo46,53–56.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [54]
Both FGF21 and another endocrine FGF, FGF15/19, share a requirement for KLB for signaling.
“Interestingly, both FGF21 and another endocrine FGF, FGF15/19, share a requirement for KLB for signaling46,54, but what cross-talk, if any, exists between these signalling pathways in both physiological and pharmacological settings is unclear.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [54]
Endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is β-klotho.
“Importantly, since FGF receptors are ubiquitously expressed, endocrine FGFs require a coreceptor to provide signaling specificity, which for FGF21 and FGF19 is the coreceptor β-klotho (71, 99, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [140]
FGF21 functions in target tissues that express FGFR1c and the obligate coreceptor β-klotho.
“FGF21 functions in target tissues that express the traditional FGF receptor FGFR1c and the obligate coreceptor β-klotho (2, 27, 71, 99, 124, 140).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [140]
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- Authors
- Wu, X., Ge, H., Gupte, J., Weiszmann, J., Shimamoto, G., Stevens, J., Hawkins, N., Lemon, B., Shen, W., Xu, J., Veniant, M. M., Li, Y.-S., Lindberg, R., Chen, J.-L., Tian, H., & Li, Y.
- Affiliations
- Amgen (United States) (US)
- Corresponding author
- Li, Yang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 282
- Issue
- 40
- Pages
- 29069-29072
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2039992462
- Cited by
- 140
- References
- 24
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 12 · 2021: 7 · 2020: 4 · 2019: 3 · 2018: 8 · 2017: 6 · 2016: 10 · 2015: 7 · 2014: 6 · 2013: 11 · 2012: 18
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- FGF19, co-receptors, β-Klotho, alpha-klotho, FGFR4, ERK1/2 phosphorylation, heparan sulfate, bile acid homeostasis, FGF receptor signaling
- MeSH terms
- Klotho Proteins, Cell Line, Endocrine System, Fibroblast Growth Factors, Gene Expression Regulation, Glucuronidase, Heparan Sulfate, Humans, Phosphorylation, Transfection, Signal Transduction, Culture Media, Conditioned, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3
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