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βKlotho Is Required for Fibroblast Growth Factor (FGF) 21 Signaling through FGF Receptor (FGFR) 1c and FGFR3c
Open accessAbstract
Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor (FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that betaKlotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of betaKlotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to betaKlotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of betaKlotho/Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter (GLUT) expression by FGF21 was associated with expression of betaKlotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that betaKlotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.
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“FGF21 elicits its biological effects by binding and activating a receptor complex composed of the co-receptor KLB and a traditional FGF receptor, fibroblast growth factor receptor 1c (FGFR1c)46,47.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [47]
In the citing paper
“FGF21 signals to a receptor complex comprised of FGF receptor 1c (FGFR1c) and its co-receptor β-klotho (KLB) [[143], [144], [145], [146]].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [144]
In the citing paper
“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 [124]
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Metadata
- Authors
- Suzuki, M., Uehara, Y., Motomura-Matsuzaka, K., Oki, J., Koyama, Y., Kimura, M., Asada, M., Komi-Kuramochi, A., Oka, S., & Toru, T.
- Affiliations
- National Institute of Advanced Industrial Science and Technology (JP)
- Tokyo University of Science (JP)
- Signaling Molecules Research Laboratory (M.S., Y.U., K.M.-M., J.O., M.K., M.A., A.K.-K., S.O., T.I.), Ibaraki 305-8566, Japan
- ORCID
- Asada, Masahiro
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2008-04-01
- Volume
- 22
- Issue
- 4
- Pages
- 1006-1014
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5419549
- OpenAlex
- W2110534048
- Cited by
- 345
- References
- 34
- Citations by year
- 2026: 17 · 2025: 16 · 2024: 18 · 2023: 11 · 2022: 18 · 2021: 18 · 2020: 19 · 2019: 19 · 2018: 13 · 2017: 25 · 2016: 26 · 2015: 25 · 2014: 16 · 2013: 20 · 2012: 27
- FWCI
- 7.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Physical Sciences › Environmental Science › Water Science and Technology › Fluoride Effects and Removal
- Keywords
- β-Klotho, FGF21, fibroblast growth factor 23, FGFR1c, FGF receptor signaling, target cell specificity, heparan sulfate proteoglycans, adipocytes, insulin-independent glucose transport, Ba/F3 cells, 3T3-L1 adipocytes, phosphate homeostasis, ketogenesis, starvation adaptation
- MeSH terms
- Fibroblast Growth Factor-23, Klotho Proteins, Animals, Fibroblast Growth Factors, Glucuronidase, Protein Binding, RNA, Messenger, Immunoblotting, Signal Transduction, Gene Expression, Reverse Transcriptase Polymerase Chain Reaction, 3T3-L1 Cells, Glucose Transport Proteins, Facilitative, Mice, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 3
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